Articles de revues : « ATP2A1 gene »

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Christodoulou, Panayiota, Andreas Yiallouris, Artemis Michail, Maria-Ioanna Christodoulou, Panagiotis K. Politis et Ioannis Patrikios. « Altered SERCA Expression in Breast Cancer ». Medicina 57, n^o 10 (8 octobre 2021) : 1074. http://dx.doi.org/10.3390/medicina57101074.

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Background and Objectives: Calcium (Ca2+) signaling is critical for the normal functioning of various cellular activities. However, abnormal changes in cellular Ca2+ can contribute to pathological conditions, including various types of cancer. The maintenance of intracellular Ca2+ levels is achieved through tightly regulated processes that help maintain Ca2+ homeostasis. Several types of regulatory proteins are involved in controlling intracellular Ca2+ levels, including the sarco/endoplasmic reticulum (SR/ER) Ca2+ ATPase pump (SERCA), which maintains Ca2+ levels released from the SR/ER. In total, three ATPase SR/ER Ca2+-transporting (ATP2A) 1-3 genes exist, which encode for several isoforms whose expression profiles are tissue-specific. Recently, it has become clear that abnormal SERCA expression and activity are associated with various types of cancer, including breast cancer. Breast carcinomas represent 40% of all cancer types that affect women, with a wide variety of pathological and clinical conditions. Materials and methods: Using cBioPortal breast cancer patient data, Kaplan–Meier plots demonstrated that high ATP2A1 and ATP2A3 expression was associated with reduced patient survival. Results: The present study found significantly different SERCA specific-type expressions in a series of breast cancer cell lines. Moreover, bioinformatics analysis indicated that ATP2A1 and ATP2A3 expression was highly altered in patients with breast cancer. Conclusion: Overall, the present data suggest that SERCA gene-specific expressioncan possibly be considered as a crucial target for the control of breast cancer development and progression.

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Li, Li, Huijuan Wu, Jialin Qian, Mingzhen Li, Yue Li, Baoming Li, Yu Han et al. « Decreased Na+/K+ ATPase α1 (ATP1A1) gene expression in major depression patients’ peripheral blood ». Open Life Sciences 8, n^o 11 (1 novembre 2013) : 1077–82. http://dx.doi.org/10.2478/s11535-013-0207-8.

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AbstractMajor depression affects the central nervous system and thereafter the autonomic nervous system, immune system, and endocrine system. Na+/K+ ATPase, as a major mediator of cellular transmembrane ionic gradients, plays an important role in nervous signal transduction. Three types of Na+/K+ ATPase α subunit isoforms (ATP1A1, ATP1A2, and ATP1A3) are found in brain but vary in the type of cell and level of expression. It has been confirmed that reduced expression of ATP1A2 and ATP1A3 are related to depressive disorder. However, there is no reported correlation between ATP1A1 and major depression. This study investigated the potential correlation between ATP1A1 gene expression level and major depression. The expression levels of ATP1A1 gene in the peripheral circulation of both depressive patients and healthy human controls were quantified by using reverse transcripted quantitative polymerase chain reaction. Statistical analysis showed a significant decrease of ATP1A1 expression level in major depression patients when compared to that of healthy controls (P<0.01). The differences of gene nucleotide sequences and protein structures among ATP1A1, ATP1A2, and ATP1A3 were also illustrated. This study demonstrates, for the first time, that ATP1A1 gene expression level is significantly associated with major depression and suggests that ATP1A1 could be a significant molecular marker for diagnosis.

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Autry, Joseph M., Christine B. Karim, Sudeep Perumbakkam, Carrie J. Finno, Erica C. McKenzie, David D. Thomas et Stephanie J. Valberg. « Sarcolipin Exhibits Abundant RNA Transcription and Minimal Protein Expression in Horse Gluteal Muscle ». Veterinary Sciences 7, n^o 4 (13 novembre 2020) : 178. http://dx.doi.org/10.3390/vetsci7040178.

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Ca2+ regulation in equine muscle is important for horse performance, yet little is known about this species-specific regulation. We reported recently that horse encode unique gene and protein sequences for the sarcoplasmic reticulum (SR) Ca2+-transporting ATPase (SERCA) and the regulatory subunit sarcolipin (SLN). Here we quantified gene transcription and protein expression of SERCA and its inhibitory peptides in horse gluteus, as compared to commonly-studied rabbit skeletal muscle. RNA sequencing and protein immunoblotting determined that horse gluteus expresses the ATP2A1 gene (SERCA1) as the predominant SR Ca2+-ATPase isoform and the SLN gene as the most-abundant SERCA inhibitory peptide, as also found in rabbit skeletal muscle. Equine muscle expresses an insignificant level of phospholamban (PLN), another key SERCA inhibitory peptide expressed commonly in a variety of mammalian striated muscles. Surprisingly in horse, the RNA transcript ratio of SLN-to-ATP2A1 is an order of magnitude higher than in rabbit, while the corresponding protein expression ratio is an order of magnitude lower than in rabbit. Thus, SLN is not efficiently translated or maintained as a stable protein in horse muscle, suggesting a non-coding role for supra-abundant SLN mRNA. We propose that the lack of SLN and PLN inhibition of SERCA activity in equine muscle is an evolutionary adaptation that potentiates Ca2+ cycling and muscle contractility in a prey species domestically selected for speed.

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Kong, Jie, Siming Sun, Fei Min, Xingli Hu, Yuan Zhang, Yan Cheng, Haiyan Li, Xiaojie Wang et Xin Liu. « Integrating Network Pharmacology and Transcriptomic Strategies to Explore the Pharmacological Mechanism of Hydroxysafflor Yellow A in Delaying Liver Aging ». International Journal of Molecular Sciences 23, n^o 22 (18 novembre 2022) : 14281. http://dx.doi.org/10.3390/ijms232214281.

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Aging affects the structure and function of the liver. Hydroxysafflor yellow A (HSYA) effectively improves liver aging (LA) in mice, but the potential mechanisms require further exploration. In this study, an integrated approach combining network pharmacology and transcriptomics was used to elucidate the potential mechanisms of HSYA delay of LA. The targets of HSYA were predicted using the PharmMapper, SwissTargetPrediction, and CTD databases, and the targets of LA were collected from the GeneCards database. An ontology (GO) analysis and a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation of genes related to HSYA delay of LA were performed using the DAVID database, and Cytoscape software was used to construct an HSYA target pathway network. The BMKCloud platform was used to sequence mRNA from mouse liver tissue, screen differentially expressed genes (DEGs) that were altered by HSYA, and enrich their biological functions and signaling pathways through the OmicShare database. The results of the network pharmacology and transcriptomic analyses were combined. Then, quantitative real-time PCR (qRT-PCR) and Western blot experiments were used to further verify the prediction results. Finally, the interactions between HSYA and key targets were assessed by molecular docking. The results showed that 199 potentially targeted genes according to network pharmacology and 480 DEGs according to transcriptomics were involved in the effects of HSYA against LA. An integrated analysis revealed that four key targets, including HSP90AA1, ATP2A1, NOS1 and CRAT, as well as their three related pathways (the calcium signaling pathway, estrogen signaling pathway and cGMP–PKG signaling pathway), were closely related to the therapeutic effects of HSYA. A gene and protein expression analysis revealed that HSYA significantly inhibited the expressions of HSP90AA1, ATP2A1 and NOS1 in the liver tissue of aging mice. The molecular docking results showed that HSYA had high affinities with the HSP90AA1, ATP2A1 and NOS1 targets. Our data demonstrate that HSYA may delay LA in mice by inhibiting the expressions of HSP90AA1, ATP2A1 and NOS1 and regulating the calcium signaling pathway, the estrogen signaling pathway, and the cGMP–PKG signaling pathway.

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Sweadner, Kathleen J., Elena Arystarkhova, John T. Penniston, Kathryn J. Swoboda, Allison Brashear et Laurie J. Ozelius. « Genotype-structure-phenotype relationships diverge in paralogs ATP1A1, ATP1A2, and ATP1A3 ». Neurology Genetics 5, n^o 1 (février 2019) : e303. http://dx.doi.org/10.1212/nxg.0000000000000303.

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ObjectiveWe tested the assumption that closely related genes should have similar pathogenic variants by analyzing >200 pathogenic variants in a gene family with high neurologic impact and high sequence identity, the Na,K-ATPases ATP1A1, ATP1A2, and ATP1A3.MethodsData sets of disease-associated variants were compared. Their equivalent positions in protein crystal structures were used for insights into pathogenicity and correlated with the phenotype and conservation of homology.ResultsRelatively few mutations affected the corresponding amino acids in 2 genes. In the membrane domain of ATP1A3 (primarily expressed in neurons), variants producing milder neurologic phenotypes had different structural positions than variants producing severe phenotypes. In ATP1A2 (primarily expressed in astrocytes), membrane domain variants characteristic of severe phenotypes in ATP1A3 were absent from patient data. The known variants in ATP1A1 fell into 2 distinct groups. Sequence conservation was an imperfect indicator: it varied among structural domains, and some variants with demonstrated pathogenicity were in low conservation sites.ConclusionsPathogenic variants varied between genes despite high sequence identity, and there is a genotype-structure-phenotype relationship in ATP1A3 that correlates with neurologic outcomes. The absence of “severe” pathogenic variants in ATP1A2 patients predicts that they will manifest either in a different tissue or by death in utero and that new ATP1A1 variants will produce additional phenotypes. It is important that some variants in poorly conserved amino acids are nonetheless pathogenic and could be incorrectly predicted to be benign.

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Molenaar, Joery P., Jamie I. Verhoeven, Richard J. Rodenburg, Erik J. Kamsteeg, Corrie E. Erasmus, Savine Vicart, Anthony Behin et al. « Clinical, morphological and genetic characterization of Brody disease : an international study of 40 patients ». Brain 143, n^o 2 (1 février 2020) : 452–66. http://dx.doi.org/10.1093/brain/awz410.

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Abstract Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.

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Tao, Rong, Chu-Pak Lau et Gui-Rong Li. « Inositol 1,4,5-Trisphosphate Receptors Mediating Spontaneous Ca2+ Oscillation Favors Proliferation in Human Mesenchymal Stem Cells from Bone Marrow. » Blood 108, n^o 11 (16 novembre 2006) : 2572. http://dx.doi.org/10.1182/blood.v108.11.2572.2572.

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Abstract Although human mesenchymal stem cells (hMSCs) constitute a very small population of cells in bone marrow, they play an important role in the regulation of hematopoietic microenvironment. The self-renew and/or proliferation of hMSCs is believed to be particularly important in maintaining bone marrow niche; however, the regulation of this process is not fully understood. The present study was designed to investigate whether spontaneous Ca2+ oscillation mediated by inositol 1,4,5-trisphosphate (IP3) receptors participates in the proliferation regulation in cultured hMSCs from bone marrow using RT-PCR, cell proliferation assay, Western-blotting analysis. It was found that no gene expression for ryanodine-sensitive receptors was detected in undifferentiated hMSCs, while three subtypes of IP3 receptor genes (i.e. IP3R1, IP3R2, and IP3R3), and genes for sarco/endoplasmic reticulum Ca2+ ATPases (SERCA) (ATP2A1, ATP2A2, and ATP2A3) were expressed in these cells. The proliferation of hMSCs was reduced by inhibiting Ca2+ oscillation with the IP3 receptor antagonist 2-aminoethyl diphenylborinate (2-APB) or the SERCA inhibitor cyclopiazonic acid (CPA). In addition, inhibition of Mek/Erk and PI-3K/Akt signaling also decreased hMSCs proliferation. The relation of Ca2+ oscillation to the activity of these kinases was revealed by Western blotting analysis. Erk1/2 (Thr185/Tyr187) phosphorylation level was found to be reduced by directly inhibiting Ca2+ oscillation with 2-APB or CPA either in the presence or absence of serum. However, Akt (Thr308) phosphorylation was decreased only in the presence of serum, and serum-free starvation (2 h) eliminated Akt (Thr308) phosphorylation. Finally the calmodulin inhibitors W-7 and SKF-7171A were employed to further investigate whether this ubiquitous Ca2+ sensor is involved in the Ca2+ signal-mediated effect. Similarly, the phosphorylation level of Erk1/2 (Thr185/Tyr187) and Akt (Thr308) reduced upon the inhibition of calmodulin. In conclusion, our results demonstrate that IP3 receptors-mediated spontaneous Ca2+ oscillation and/or Ca2+/calmodulin signaling play(s) a crucial role in the regulation of cell proliferation mediated by multiple pro-proliferation signaling pathways (e.g. Mek/Erk and PI-3K/Akt). Importantly, Erk1/2 phosphorylation is sensitive to spontaneous Ca2+ oscillation, and therefore is responsible for the proliferation induced by Ca2+ oscillation in hMSCs.

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Kim, Kyunam, Hee Eun Kang, Jong In Yook, Hyung-Seog Yu, Euiseong Kim, Jung-Yul Cha et Yoon Jeong Choi. « Transcriptional Expression in Human Periodontal Ligament Cells Subjected to Orthodontic Force : An RNA-Sequencing Study ». Journal of Clinical Medicine 9, n^o 2 (28 janvier 2020) : 358. http://dx.doi.org/10.3390/jcm9020358.

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This study was performed to investigate the changes in gene expression in periodontal ligament (PDL) cells following mechanical stimulus through RNA sequencing. In this study, premolars extracted for orthodontic treatment were used. To stimulate the PDL cells, an orthodontic force of 100× g was applied to the premolar (experimental group; n = 11), whereas the tooth on the other side was left untreated (control group; n = 11). After the PDL cells were isolated from the extracted teeth, gene set enrichment analysis (GSEA), differentially expressed gene (DEG) analysis, and real-time PCR were performed to compare the two groups. GSEA demonstrated that gene sets related to the cell cycle pathway were upregulated in PDL. Thirteen upregulated and twenty downregulated genes were found through DEG analysis. Real-time PCR results confirmed that five upregulated genes (CC2D1B, CPNE3, OPHN1, TANGO2, and UAP-1) and six downregulated genes (MYOM2, PPM1F, PCDP1, ATP2A1, GPR171, and RP1-34H18.1-1) were consistent with RNA sequencing results. We suggest that, from among these eleven genes, two upregulated genes, CPNE3 and OPHN1, and one downregulated gene, PPM1F, play an important role in PDL regeneration in humans when orthodontic force is applied.

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Dohrn, Maike F., Adriana P. Rebelo, Siddharth Srivastava, Gerarda Cappuccio, Robert Smigiel, Alka Malhotra, Donald Basel et al. « De Novo ATP1A1 Variants in an Early-Onset Complex Neurodevelopmental Syndrome ». Neurology 98, n^o 11 (2 février 2022) : 440–45. http://dx.doi.org/10.1212/wnl.0000000000013276.

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ATP1A1 encodes the α1 subunit of the sodium-potassium ATPase, an electrogenic cation pump highly expressed in the nervous system. Pathogenic variants in other subunits of the same ATPase, encoded by ATP1A2 or ATP1A3, are associated with syndromes such as hemiplegic migraine, dystonia, or cerebellar ataxia. Worldwide, only 16 families have been reported carrying pathogenic ATP1A1 variants to date. Associated phenotypes are axonal neuropathies, spastic paraplegia, and hypomagnesemia with seizures and intellectual disability. By whole exome or genome sequencing, we identified 5 heterozygous ATP1A1 variants, c.674A>G;p.Gln225Arg, c.1003G>T;p.Gly335Cys, c.1526G>A;p.Gly509Asp, c.2152G>A;p.Gly718Ser, and c.2768T>A;p.Phe923Tyr, in 5 unrelated children with intellectual disability, spasticity, and peripheral, motor predominant neuropathy. Additional features were sensory loss, sleep disturbances, and seizures. All variants occurred de novo and are absent from control populations (MAF GnomAD = 0). Affecting conserved amino acid residues and constrained regions, all variants have high pathogenicity in silico prediction scores. In HEK cells transfected with ouabain-insensitive ATP1A1 constructs, cell viability was significantly decreased in mutants after 72h treatment with the ATPase inhibitor ouabain, demonstrating loss of ATPase function. Replicating the haploinsufficiency mechanism of disease with a gene-specific assay provides pathogenicity information and increases certainty in variant interpretation. This study further expands the genotype-phenotype spectrum of ATP1A1.

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Åkerström, Tobias, Holger Sven Willenberg, Kenko Cupisti, Julian Ip, Samuel Backman, Ana Moser, Rajani Maharjan et al. « Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas ». Endocrine-Related Cancer 22, n^o 5 (octobre 2015) : 735–44. http://dx.doi.org/10.1530/erc-15-0321.

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Aldosterone-producing adenomas (APAs) are found in 1.5–3.0% of hypertensive patients in primary care and can be cured by surgery. Elucidation of genetic events may improve our understanding of these tumors and ultimately improve patient care. Approximately 40% of APAs harbor a missense mutation in the KCNJ5 gene. More recently, somatic mutations in CACNA1D, ATP1A1 and ATP2B3, also important for membrane potential/intracellular Ca2+ regulation, were observed in APAs. In this study, we analyzed 165 APAs for mutations in selected regions of these genes. We then correlated mutational findings with clinical and molecular phenotype using transcriptome analysis, immunohistochemistry and semiquantitative PCR. Somatic mutations in CACNA1D in 3.0% (one novel mutation), ATP1A1 in 6.1% (six novel mutations) and ATP2B3 in 3.0% (two novel mutations) were detected. All observed mutations were located in previously described hotspot regions. Patients with tumors harboring mutations in CACNA1D, ATP1A1 and ATP2B3 were operated at an older age, were more often male and had tumors that were smaller than those in patients with KCNJ5 mutated tumors. Microarray transcriptome analysis segregated KCNJ5 mutated tumors from ATP1A1/ATP2B3 mutated tumors and those without mutation. We observed significant transcription upregulation of CYP11B2, as well as the previously described glomerulosa-specific gene NPNT, in ATP1A1/ATP2B3 mutated tumors compared to KCNJ5 mutated tumors. In summary, we describe novel somatic mutations in proteins regulating the membrane potential/intracellular Ca2+ levels, and also a distinct mRNA and clinical signature, dependent on genetic alteration.

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Motahari-Rad, Hanieh, Alba Subiri, Rocio Soler, Luis Ocaña, Juan Alcaide, Jorge Rodríguez-Capitan, Veronica Buil et al. « The Effect of Sex and Obesity on the Gene Expression of Lipid Flippases in Adipose Tissue ». Journal of Clinical Medicine 11, n^o 13 (4 juillet 2022) : 3878. http://dx.doi.org/10.3390/jcm11133878.

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Molecular mechanisms behind obesity and sex-related effects in adipose tissue remain elusive. During adipocyte expansion, adipocytes undergo drastic remodelling of lipid membrane compositions. Lipid flippases catalyse phospholipid translocation from exoplasmic to the cytoplasmic leaflet of membranes. The present study aimed to analyse the effect of sex, obesity, and their interactions on the gene expression of two lipid flippases—ATP8A1 and ATP8B1—and their possible microRNA (miR) modulators in visceral adipose tissue (VAT). In total, 12 normal-weight subjects (5 premenopausal women and 7 men) and 13 morbidly obese patients (7 premenopausal women and 6 men) were submitted to surgery, and VAT samples were obtained. Gene expression levels of ATP8A1, ATP8B1, miR-548b-5p, and miR-4643 were measured in VAT. Our results showed a marked influence of obesity on VAT ATP8A1 and ATP8B1, although the effects of obesity were stronger in men for ATP8A1. Both genes positively correlated with obesity and metabolic markers. Furthermore, ATP8B1 was positively associated with miR-548b-5p and negatively associated with miR-4643. Both miRs were also affected by sex. Thus, lipid flippases are altered by obesity in VAT in a sex-specific manner. Our study provides a better understanding of the sex-specific molecular mechanisms underlying obesity, which may contribute to the development of sex-based precision medicine.

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Wang, Xi, Chang Kong, Pan Liu, Wujun Geng et Hongli Tang. « Identification of Potential Biomarkers for Ryanodine Receptor 1 (RYR1) Mutation-Associated Myopathies Using Bioinformatics Approach ». Disease Markers 2022 (23 mai 2022) : 1–11. http://dx.doi.org/10.1155/2022/8787782.

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Background. Myopathies related to Ryanodine receptor 1 (RYR1) mutation are the most common nondystrophy muscle disorder in humans. Early detection and diagnosis of RYR1 mutation-associated myopathies may lead to more timely treatment of patients, which contributes to the management and preparation for malignant hyperthermia. However, diagnosis of RYR1 mutation-associated myopathies is delayed and challenging. The absence of diagnostic morphological features in muscle biopsy does not rule out the possibility of pathogenic variations in RYR1. Accordingly, it is helpful to seek biomarkers to diagnose RYR1 mutation-associated myopathies. Methods. Skeletal muscle tissue microarray datasets of RYR1 mutation-associated myopathies or healthy persons were built in accordance with the gene expression synthesis (GEO) database. Differentially expressed genes (DEGs) were identified on the basis of R software. Genes specific to tissue/organ were identified through BioGPS. An enrichment analysis of DEGs was conducted in accordance with the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). We also built protein-protein interaction (PPI) networks to explore the function and enrichment pathway of DEGs and the identification of hub genes. Lastly, the ROC curve was drawn for hub genes achieving specific expressions within skeletal muscle. Moreover, the area under the curve (AUC) was obtained to calculate the predictive value of key genes. The transcription factors of hub genes achieving specific expressions within skeletal muscle were predicted with the use of the iRegulon plugin. Results. We identified 170 DEGs among 11 healthy subject samples and 18 RYR1 mutation-associated myopathy samples in the dataset. Among the above DEGs, 31 genes achieving specific expressions within tissues/organs were found. GO and KEGG enrichment analysis of DEGs mainly focused on muscle contraction, actin-mediated cell contraction, actin filament-based movement, and muscular sliding. 12 hub genes were identified with the use of Cytoscape. Four hub genes were specifically expressed in skeletal muscle tissue, including MYH1 (AUC: 0.856), TNNT3 (AUC: 0.840), MYLPF (AUC: 0.786), and ATP2A1 (AUC: 0.765). The iRegulon predicted results suggested that the transcription factor MYF6 was found with the highest reliability. Conclusions. Four skeletal muscle tissue-specific genes were identified, including MYH1, TNNT3, MYLPF, and ATP2A1, as the potential biomarkers for diagnosing and treating RYR1 mutation-associated myopathies, which provided insights into the transcriptome-level development mechanism. The transcription factor MYF6 may be a vital upstream regulator of the above biomarkers.

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Ciobanu, D. C., Y. Zhang et M. F. Rothschild. « Rapid communication : mapping of the Ca2+ATPase of fast twitch 1 skeletal muscle sarcoplasmic reticulum (ATP2A1) gene to porcine chromosome 3 ». Journal of Animal Science 80, n^o 5 (1 mai 2002) : 1386–87. http://dx.doi.org/10.2527/2002.8051386x.

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Drögemüller, Cord, Michaela Drögemüller, Tosso Leeb, Francesco Mascarello, Stefania Testoni, Marco Rossi, Arcangelo Gentile, Ernesto Damiani et Roberta Sacchetto. « Identification of a missense mutation in the bovine ATP2A1 gene in congenital pseudomyotonia of Chianina cattle : An animal model of human Brody disease ». Genomics 92, n^o 6 (décembre 2008) : 474–77. http://dx.doi.org/10.1016/j.ygeno.2008.07.014.

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Maclennan, DAVID H., WILLIAM J. RICE et ALEX ODERMATT. « Structure/Function Analysis of the Ca2+Binding and Translocation Domain of SERCA1 and the Role in Brody Disease of the ATP2A1 Gene Encoding SERCA1 ». Annals of the New York Academy of Sciences 834, n^o 1 Na/K-ATPase a (novembre 1997) : 175–85. http://dx.doi.org/10.1111/j.1749-6632.1997.tb52249.x.

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Akyürek, Eylem Emek, Francesca Busato, Leonardo Murgiano, Elisa Bianchini, Marcello Carotti, Dorianna Sandonà, Cord Drögemüller, Arcangelo Gentile et Roberta Sacchetto. « Differential Analysis of Gly211Val and Gly286Val Mutations Affecting Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA1) in Congenital Pseudomyotonia Romagnola Cattle ». International Journal of Molecular Sciences 23, n^o 20 (15 octobre 2022) : 12364. http://dx.doi.org/10.3390/ijms232012364.

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Congenital pseudomyotonia in cattle (PMT) is a rare skeletal muscle disorder, clinically characterized by stiffness and by delayed muscle relaxation after exercise. Muscle relaxation impairment is due to defective content of the Sarco(endo)plasmic Reticulum Ca2+ ATPase isoform 1 (SERCA1) protein, caused by missense mutations in the ATP2A1 gene. PMT represents the only mammalian model of human Brody myopathy. In the Romagnola breed, two missense variants occurring in the same allele were described, leading to Gly211Val and Gly286Val (G211V/G286V) substitutions. In this study, we analyzed the consequences of G211V and G286V mutations. Results support that the reduced amount of SERCA1 is a consequence of the G211V mutation, the G286V mutation almost being benign and the ubiquitin–proteasome system (UPS) being involved. After blocking the proteasome using a proteasome inhibitor, we found that the G211V mutant accumulates in cells at levels comparable to those of WT SERCA1. Our conclusion is that G211/286V mutations presumably originate in a folding-defective SERCA1 protein, recognized and diverted to degradation by UPS, although still catalytically functional, and that the main role is played by G211V mutation. Rescue of mutated SERCA1 to the sarcoplasmic reticulum membrane can re-establish resting cytosolic Ca2+ concentration and prevent the appearance of pathological signs, paving the way for a possible therapeutic approach against Brody disease.

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Ikeda, Keiko, Adriana A. Tienda, Fiona E. Harrison et Kiyoshi Kawakami. « Decreased content of ascorbic acid (vitamin C) in the brain of knockout mouse models of Na+,K+-ATPase-related neurologic disorders ». PLOS ONE 16, n^o 2 (5 février 2021) : e0246678. http://dx.doi.org/10.1371/journal.pone.0246678.

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Na+,K+-ATPase is a crucial protein responsible for maintaining the electrochemical gradients across the cell membrane. The Na+,K+-ATPase is comprised of catalytic α, β, and γ subunits. In adult brains, the α3 subunit, encoded by ATP1A3, is predominantly expressed in neurons, whereas the α2 subunit, encoded by ATP1A2, is expressed in glial cells. In foetal brains, the α2 is expressed in neurons as well. Mutations in α subunits cause a variety of neurologic disorders. Notably, the onset of symptoms in ATP1A2- and ATP1A3-related neurologic disorders is usually triggered by physiological or psychological stressors. To gain insight into the distinct roles of the α2 and α3 subunits in the developing foetal brain, whose developmental dysfunction may be a predisposing factor of neurologic disorders, we compared the phenotypes of mouse foetuses with double homozygous knockout of Atp1a2 and Atp1a3 (α2α3-dKO) to those with single knockout. The brain haemorrhage phenotype of α2α3-dKO was similar to that of homozygous knockout of the gene encoding ascorbic acid (ASC or vitamin C) transporter, SVCT2. The α2α3-dKO brain showed significantly decreased level of ASC compared with the wild-type (WT) and single knockout. We found that the ASC content in the basal ganglia and cerebellum was significantly lower in the adult Atp1a3 heterozygous knockout mouse (α3-HT) than in the WT. Interestingly, we observed a significant decrease in the ASC level in the basal ganglia and cerebellum of α3-HT in the peripartum period, during which mice are under physiological stress. These observations indicate that the α2 and α3 subunits independently contribute to the ASC level in the foetal brain and that the α3 subunit contributes to ASC transport in the adult basal ganglia and cerebellum. We propose that decreases in ASC levels may affect neural network development and are linked to the pathophysiology of ATP1A2- and ATP1A3-related neurologic disorders.

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Linek, Monika, Maren Doelle, Tosso Leeb, Anina Bauer, Fabienne Leuthard, Jan Henkel, Danika Bannasch, Vidhya Jagannathan et Monika M. Welle. « ATP2A2 SINE Insertion in an Irish Terrier with Darier Disease and Associated Infundibular Cyst Formation ». Genes 11, n^o 5 (28 avril 2020) : 481. http://dx.doi.org/10.3390/genes11050481.

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A 4-month-old female Irish Terrier presented with a well demarcated ulcerative and crusting lesion in the right ear canal. Histological analysis revealed epidermal hyperplasia with severe acantholysis affecting all suprabasal layers of the epidermis, which prompted a presumptive diagnosis of canine Darier disease. The lesion was successfully treated by repeated laser ablation of the affected epidermis. Over the course of three years, the dog additionally developed three dermal nodules of up to 4 cm in diameter that were excised and healed without complications. Histology of the excised tissue revealed multiple infundibular cysts extending from the upper dermis to the subcutis. The cysts were lined by squamous epithelium, which presented with abundant acantholysis of suprabasal keratinocytes. Infundibular cysts represent a novel finding not previously reported in Darier patients. Whole genome sequencing of the affected dog was performed, and the functional candidate genes for Darier disease (ATP2A2) and Hailey-Hailey disease (ATP2C1) were investigated. The analysis revealed a heterozygous SINE insertion into the ATP2A2 gene, at the end of intron 14, close to the boundary of exon 15. Analysis of the ATP2A2 mRNA from skin of the affected dog demonstrated a splicing defect and marked allelic imbalance, suggesting nonsense-mediated decay of the resulting aberrant transcripts. As Darier disease in humans is caused by haploinsufficiency of ATP2A2, our genetic findings are in agreement with the clinical and histopathological data and support the diagnosis of canine Darier disease.

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Ellegren, Hans, et Ariane Carmichael. « Multiple and Independent Cessation of Recombination Between Avian Sex Chromosomes ». Genetics 158, n^o 1 (1 mai 2001) : 325–31. http://dx.doi.org/10.1093/genetics/158.1.325.

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Abstract Birds are characterized by female heterogamety; females carry the Z and W sex chromosomes, while males have two copies of the Z chromosome. We suggest here that full differentiation of the Z and W sex chromosomes of birds did not take place until after the split of major contemporary lineages, in the late Cretaceous. The ATP synthase α-subunit gene is now present in one copy each on the nonrecombining part of the W chromosome (ATP5A1W) and on the Z chromosome (ATP5A1Z). This gene seems to have evolved on several independent occasions, in different lineages, from a state of free recombination into two sex-specific and nonrecombining variants. ATP5A1W and ATP5A1Z are thus more similar within orders, relative to what W (or Z) are between orders. Moreover, this cessation of recombination apparently took place at different times in different lineages (estimated at 13, 40, and 65 million years ago in Ciconiiformes, Galliformes, and Anseriformes, respectively). We argue that these observations are the result of recent and traceable steps in the process where sex chromosomes gradually cease to recombine and become differentiated. Our data demonstrate that this process, once initiated, may occur independently in parallel in sister lineages.

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MOHAMMED NAZRI, SITI KHADIJAH SYED, et ELENA AISHA AZIZAN. « SECONDARY HYPERTENSION : GENES THAT STIMULATE EXCESSIVE SECRETION OF ALDOSTERONE ». Jurnal Sains Kesihatan Malaysia 20, n^o 1 (1 janvier 2022) : 51–63. http://dx.doi.org/10.17576/jskm-2022-2001-05.

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Hypertension is highly prevalent in Malaysia and even the rest of the world. Primary aldosteronism (PA) is one of the most common treatable cause of secondary hypertension. PA occurs due to excessive secretion of aldosterone in the adrenal glands. Up to one in five resistant hypertension cases are due to PA. Therefore, there are a high number of individuals who have the potential to be cured of their hypertension. However, this is difficult to achieve due to limitations in the procedure of diagnosing the PA disease. The challenge now is to know the best usage of available diagnostic methods to detect those who would most likely be cured of hypertension which may be associated with the genotype of the disease. In the past decade, five genes have been found to cause excess aldosterone production in aldosteroneproducing adenomas (APAs), namely KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1. These somatic mutations have been found to activate the intracellular signaling pathway that regulates aldosterone production. Studies on bilateral adrenal hyperplasia (BAH) samples also have identified the genetic causes for the many hereditary hyperaldosteronism, namely familial hyperaldosteronism types I, II, III, and IV/V. Herein we review the genetic factors of PA as a result of either aldosterone-stimulating somatic mutations or germline variants, and the associated clinical phenotype.

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da Silva, Aghata Elins Moreira, Arturo Macias Franco, Felipe Henrique De Moura, Bradley S. Ferguson et Mozart Fonseca. « 322 The Influence of Previous Plane of Nutrition on Grain or Grass-fed Finished Steers : Water-Related Gene Expression in the Kidney ». Journal of Animal Science 100, Supplement_3 (21 septembre 2022) : 155. http://dx.doi.org/10.1093/jas/skac247.288.

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Abstract The extenuating stressors inherent to various beef cattle backgrounding systems in the U. S. may imprint different nutritional carryover effects of earlier stages of life onto the finishing phase. Therefore, the objective of this study was to evaluate the effects of previous plane of nutrition (PPN) onto water-related gene expression in the kidney of grain or grass finished steers. Twenty-four crossbred Angus steers were randomly distributed into either low or adequate PPN during the background phase. After 85d of backgrounding, animals were moved onto a 105-d finishing phase blocked by their PPN. The grass-finished group received only alfalfa hay, whereas the grain-finished group received a high grain diet (80% whole corn and 20% alfalfa hay). By the end of the finishing phase, animals were harvested and kidney samples were collected. Changes in gene expression of Aquaporins (AQP) -2, -3, -4, -7, ATP1A1, ATP1B1, SGK1, and CLIC1 from kidney tissue were assayed via real-time qPCR; and the 18S rRNA was used as an endogenous control. One-way ANOVA followed by Tukey post hoc analysis were conducted. When comparing grain versus grass-finished according to their PPN, ATP1B1 (P = 0.0290) was the only gene significantly different, with animals coming from a low PPN finished on grass having greater expression than for the grain-finished. However, within animals backgrounded at a low PPN, AQP3 (P = 0.0289), AQP7 (P = 0.0260), ATP1B1 (P = 0.0239), and SGK1 (P = 0.0411) were upregulated for the grass-finished animals. No differences were found for the other genes analyzed. These results suggest that PPN can impact water-related gene expression in the kidney of finishing steers; the greatest impact for water-related gene expression occurred in animals from a low PPN that were fed different finishing systems, where grass-fed animals had a greater gene expression compared with grain-fed animals.

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Ngo, Jennifer, et Richard Haber. « Exacerbation of Darier Disease by Lithium Carbonate ». Journal of Cutaneous Medicine and Surgery 14, n^o 2 (mars 2010) : 80–84. http://dx.doi.org/10.2310/7750.2009.08067.

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Introduction: Darier disease (DD) and Hailey-Hailey disease (HHD) are rare autosomal dominantly inherited genodermatoses with mutations in the respective genes, ATP2A2 and ATP2C1, that encode the respective calcium adenosine triphosphatases SERCA2 and PMRI/SPCA1. Lithium is an effective therapy used in psychiatry as prophylaxis against recurrent mania and to treat acute schizoaffective, impulsive, and alcoholic disorders. Methods: We discuss a patient with DD who claimed that her skin condition had flared after she was administered lithium therapy for bipolar disorder. Discussion and Conclusions: DD may flare after lithium therapy, an association that has rarely been reported. Not uncommonly, DD has been observed to coexist with affective disorders, with reports of the bipolar disorder susceptibility locus cosegregating with a separate DD gene. A mechanism by which lithium worsens disease has recently been studied in rats. DD's coexistence with affective disorders and the mechanisms by which lithium may cause exacerbation of DD and HHD are reviewed.

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Fan, Xiaoming, Usman Ashraf, Christopher Drummond, Huilin Shi, Xiaolu Zhang, Sivarajan Kumarasamy et Jiang Tian. « Characterization of a Long Non-Coding RNA, the Antisense RNA of Na/K-ATPase α1 in Human Kidney Cells ». International Journal of Molecular Sciences 19, n^o 7 (21 juillet 2018) : 2123. http://dx.doi.org/10.3390/ijms19072123.

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Non-coding RNAs are important regulators of protein-coding genes. The current study characterized an antisense long non-coding RNA, ATP1A1-AS1, which is located on the opposite strand of the Na/K-ATPase α1 gene. Our results show that four splice variants are expressed in human adult kidney cells (HK2 cells) and embryonic kidney cells (HEK293 cells). These variants can be detected in both cytosol and nuclear fractions. We also found that the inhibition of DNA methylation has a differential effect on the expression of ATP1A1-AS1 and its sense gene. To investigate the physiological role of this antisense gene, we overexpressed the ATP1A1-AS1 transcripts, and examined their effect on Na/K-ATPase expression and related signaling function in human kidney cells. The results showed that overexpression of the ATP1A1-AS1-203 transcript in HK2 cells reduced the Na/K-ATPase α1 (ATP1A1) gene expression by approximately 20% (p < 0.05), while reducing the Na/K-ATPase α1 protein synthesis by approximately 22% (p < 0.05). Importantly, overexpression of the antisense RNA transcript attenuated ouabain-induced Src activation in HK2 cells. It also inhibited the cell proliferation and potentiated ouabain-induced cell death. These results demonstrate that the ATP1A1-AS1 gene is a moderate negative regulator of Na/K-ATPase α1, and can modulate Na/K-ATPase-related signaling pathways in human kidney cells.

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Elayadeth-Meethal, Muhammed, Aravindakshan Thazhathu Veettil, Muhasin Asaf, Sathiamoorthy Pramod, Shane K. Maloney, Graeme B. Martin, M. Jordana Rivero et al. « Comparative Expression Profiling and Sequence Characterization of ATP1A1 Gene Associated with Heat Tolerance in Tropically Adapted Cattle ». Animals 11, n^o 8 (11 août 2021) : 2368. http://dx.doi.org/10.3390/ani11082368.

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Climate change is an imminent threat to livestock production. One adaptation strategy is selection for heat tolerance. While it is established that the ATP1A1 gene and its product play an important role in the response to many stressors, there has been no attempt to characterize the sequence or to perform expression profiling of the gene in production animals. We undertook a field experiment to compare the expression profiles of ATP1A1 in heat-tolerant Vechur and Kasaragod cattle (Bos taurus indicus) with the profile of a heat-susceptible crossbreed (B. t. taurus × B. t. indicus). The cattle were exposed to heat stress while on pasture in the hot summer season. The environmental stress was quantified using the temperature humidity index (THI), while the heat tolerance of each breed was assessed using a heat tolerance coefficient (HTC). The ATP1A1 mRNA of Vechur cattle was amplified from cDNA and sequenced. The HTC varied significantly between the breeds and with time-of-day (p < 0.01). The breed–time-of-day interaction was also significant (p < 0.01). The relative expression of ATP1A1 differed between heat-tolerant and heat-susceptible breeds (p = 0.02). The expression of ATP1A1 at 08:00, 10:00 and 12:00, and the breed–time-of-day interaction, were not significant. The nucleotide sequence of Vechur ATP1A1 showed 99% homology with the B. t. taurus sequence. The protein sequence showed 98% homology with B. t. taurus cattle and with B. grunniens (yak) and 97.7% homology with Ovis aries (sheep). A molecular clock analysis revealed evidence of divergent adaptive evolution of the ATP1A1 gene favoring climate resilience in Vechur cattle. These findings further our knowledge of the relationship between the ATP1A1 gene and heat tolerance in phenotypically incongruent animals. We propose that ATP1A1 could be used in marker assisted selection (MAS) for heat tolerance.

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Micaroni, Massimo. « Misinterpretation of ATP2C1 gene mutations ». Indian Journal of Dermatology, Venereology, and Leprology 82, n^o 3 (2016) : 306. http://dx.doi.org/10.4103/0378-6323.175922.

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Song, BA, Yisa, Fei Wang, MA, Yaxun Wei, MA, Dong Chen, BA et Gang Deng, BA. « ATP5A1 Participates in Transcriptional and Posttranscriptional Regulation of Cancer-Associated Genes by Modulating Their Expression and Alternative Splicing Profiles in HeLa Cells ». Technology in Cancer Research & ; Treatment 20 (janvier 2021) : 153303382110391. http://dx.doi.org/10.1177/15330338211039126.

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Background: Aberrant expression and alternative splicing of oncogenes are the driving events in tumor initiation and development. But how these events are regulated in cancer cells is largely unknown. Functions of ATP5A1, an important mitochondrial ATP synthase gene, in transcriptional and posttranscriptional regulation were explored in this study. Methods: ATP5A1 was overexpressed using plasmid-transformed HeLa cells, and its influence on cell apoptosis and proliferation is evaluated. Transcriptome sequencing was then performed using RNA-seq to study the changes in gene expression and regulation of alternative splicing events. Validation of the implicated genes was achieved using RT-qPCR analysis. Results: It was found that ATP5A1 could significantly promote cellular apoptosis, but it had no influence on cell proliferation. ATP5A1 overexpression significantly increased the expression levels of genes associated with the innate immune response, angiogenesis, and collagen catabolic processes. This included enrichment of MMP2 and MMP19. It was also found that ATP5A1 could interfere with the alternative splicing of hundreds of genes associated with glucose homeostasis, HIF-1 signaling activation, and several pathways associated with cancers. Eight ATP5A1-regulated differentially expressed genes and 3 genes altered by splicing were selected and validated using RT-qPCR analysis. Conclusions: In summary, we illustrate the regulatory functions of ATP5A1 on the transcriptome of HeLa cells by exploring its influence on gene expression and alternative splicing. The results suggest that ATP5A1 may play an important regulatory role in cervical cancer cells by regulating expression and alternative splicing of cancer-associated genes. This study provides novel insights into the current understanding of the mechanisms of ATP5A1 on carcinogenesis and cancer progression.

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Xiao, Zhen, Zhi-Gang Liu, Xiao-Liang Ou Yang, Si-Min Yu, Jian-rong Zeng et Chun-Ming Li. « Two Novel Variants and One Previously Reported Variant in the ATP2C1 Gene in Chinese Hailey-Hailey Disease Patients ». Molecular Syndromology 12, n^o 3 (2021) : 148–53. http://dx.doi.org/10.1159/000514282.

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Hailey-Hailey disease (HHD) is a rare autosomal dominant genodermatosis. It is characterized clinically by recurrent erosions, blisters and erythematous plaques at the sites of friction and intertriginous areas. The pathogenic gene of HHD was reported to be the ATPase calcium-transporting type 2C member 1 gene (ATP2C1). In this study, genomic DNA polymerase chain reaction (PCR) and direct sequencing of ATP2C1 were performed from 3 Chinese pedigrees and 4 sporadic cases of HHD. We detected 3 heterozygous mutations, including 2 novel mutations (c.1673_1674insGTTG and c.2225A>G) and 1 recurrent nonsense mutation (c.1402C>T; NM_014382.4). The ATP2C1 gene was also screened in the asymptomatic members of pedigrees. Our results would further expand the mutation spectrum of the ATP2C1 gene and be helpful in the genetic counseling of patients with HHD.

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Prihandini, P. W., A. P. Z. N. L. Sari, Y. N. Anggraeni, S. Irmawanti et B. Tiesnamurti. « The ATP1A1 Gene Polymorphisms in Indonesian Beef Cattle ». IOP Conference Series : Earth and Environmental Science 1114, n^o 1 (1 décembre 2022) : 012076. http://dx.doi.org/10.1088/1755-1315/1114/1/012076.

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Abstract In this research, the direct sequencing method was used to identify the polymorphism and genetic diversity of the ATP1A1 gene in Indonesian beef cattle. The study used five breeds of local beef cattle with a total of 60 DNA samples (POGASI = 20, Jabres = 10, Bali = 10, Galekan = 10, and Madura = 10). The amplification of the ATP1A1 gene was using one set of primers (F = 5′- AGG GGT AGC CAG AGT TCC TA – 3′ and R = 5′ – CCC AAA GGT CAC GTG CTT TT – 3′). The result showed 6 SNPs in the APT1A1 gene, namely SNPs g.17293G/A, g.17356C/T, g.17359G/A, g.17541A/G, g.17585 A/G, and g. 17682C/T. Three SNPs were located in coding sequence nine, and the other SNPs were in intron 9 of the ATP1A1 gene. Based on the total population, the Chi-square test indicated that only two polymorphic loci (.17585 A/G and g. 17682C/T) fitted Hardy-Weinberg equilibrium (χ2<5.99). In conclusion, the polymorphic loci of the ATP1A1 gene can be used for genetic diversity and further association study to anti-heat stress traits of Indonesian beef cattle.

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Guo, Zeng, Kazutaka Nanba, Aaron Udager, Brett C. McWhinney, Jacobus P. J. Ungerer, Martin Wolley, Moe Thuzar, Richard D. Gordon, William E. Rainey et Michael Stowasser. « Biochemical, Histopathological, and Genetic Characterization of Posture-Responsive and Unresponsive APAs ». Journal of Clinical Endocrinology & ; Metabolism 105, n^o 9 (9 juin 2020) : e3224-e3235. http://dx.doi.org/10.1210/clinem/dgaa367.

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Abstract Context and Objective Posture-responsive and posture-unresponsive aldosterone-producing adenomas (APAs) account for approximately 40% and 60% of APAs, respectively. Somatic gene mutations have been recently reported to exist in approximately 90% of APAs. This study was designed to characterize the biochemical, histopathologic, and genetic properties of these 2 types of APA. Methods Plasma levels of aldosterone and hybrid steroids (18-oxocortisol and 18-hydroxycortisol) were measured by liquid chromatography-tandem mass spectrometry. Immunohistochemistry for CYP11B2 (aldosterone synthase) and CYP17A1 (17α-hydroxylase) and deoxyribonucleic acid sequencing (Sanger and next-generation sequencing) were performed on APA tissue collected from 23 posture-unresponsive and 17 posture-responsive APA patients. Results Patients with posture-unresponsive APA displayed higher (P < 0.01) levels of hybrid steroids, recumbent aldosterone and cortisol, larger (P < 0.01) zona fasciculata (ZF)-like tumors with higher (P < 0.01) expression of CYP17A1 (but not of CYP11B2) than patients with posture-responsive APA (most of which were not ZF-like). Of 40 studied APAs, 37 (92.5%) were found to harbor aldosterone-driving somatic mutations (KCNJ5 = 14 [35.0%], CACNA1D = 13 [32.5%], ATP1A1 = 8 [20.0%], and ATP2B3 = 2 [5.0%]), including 5 previously unreported mutations (3 in CACNA1D and 2 in ATP1A1). Notably, 64.7% (11/17) of posture-responsive APAs carried CACNA1D mutations, whereas 56.5% (13/23) of posture-unresponsive APAs harbored KCNJ5 mutations. Conclusions The elevated production of hybrid steroids by posture-unresponsive APAs may relate to their ZF-like tumor cell composition, resulting in expression of CYP17A1 (in addition to somatic gene mutation-driven CYP11B2 expression), thereby allowing production of cortisol, which acts as the substrate for CYP11B2-generated hybrid steroids.

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Herman, Maryann B., Trivikram Rajkhowa, Facundo Cutuli, James E. Springate et Mary Taub. « Regulation of renal proximal tubule Na-K-ATPase by prostaglandins ». American Journal of Physiology-Renal Physiology 298, n^o 5 (mai 2010) : F1222—F1234. http://dx.doi.org/10.1152/ajprenal.00467.2009.

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Prostaglandins (PGs) play a number of roles in the kidney, including regulation of salt and water reabsorption. In this report, evidence was obtained for stimulatory effects of PGs on Na-K-ATPase in primary cultures of rabbit renal proximal tubule (RPT) cells. The results of our real-time PCR studies indicate that in primary RPTs the effects of PGE2, the major renal PG, are mediated by four classes of PGE (EP) receptors. The role of these EP receptors in the regulation of Na-K-ATPase was examined at the transcriptional level. Na-K-ATPase consists of a catalytic α-subunit encoded by the ATP1A1 gene, as well as a β-subunit encoded by the ATP1B1 gene. Transient transfection studies conducted with pHβ1-1141 Luc, a human ATP1B1 promoter/luciferase construct, indicate that both PGE1and PGE2are stimulatory. The evidence for the involvement of both the cAMP and Ca2+signaling pathways includes the inhibitory effects of the myristolylated PKA inhibitor PKI, the adenylate cyclase (AC) inhibitor SQ22536, and the PKC inhibitors Gö 6976 and Ro-32-0432 on the PGE1stimulation. Other effectors that similarly act through cAMP and PKC were also stimulatory to transcription, including norepinephrine and dopamine. In addition to its effects on transcription, a chronic incubation with PGE1was observed to result in an increase in Na-K-ATPase mRNA levels as well as an increase in Na-K-ATPase activity. An acute stimulatory effect of PGE1on Na-K-ATPase was observed and was associated with an increase in the level of Na-K-ATPase in the basolateral membrane.

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Muslimova, E. F., T. Yu Rebrova, E. A. Archakov, Sh D. Akhmedov, O. V. Budnikova, R. E. Batalov et S. A. Afanasiev. « Polymorphic variants of genes encoding Ca(2+)-transporting sarcoplasmic reticulum proteins in the progression of chronic heart failure ». Russian Journal of Cardiology, n^o 10 (3 novembre 2019) : 48–52. http://dx.doi.org/10.15829/1560-4071-2019-10-48-52.

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Aim. To study the association between polymorphic rs1860561 variants of Ca(2+)-ATPase SERCA2a (ATP2A2) gene and rs3766871 of ryanodine receptor (RYR2) gene and the severity of chronic heart failure (CHF).Material and methods. We determined rs1860561 and rs3766871 variants of the ATP2A2 and RYR2 genes, respectively, in 168 patients with coronary artery disease (CAD) and CHF using real-time polymerase chain reaction.Results. A statistically significant (p=0,046) decrease in the left ventricular ejection fraction in AA homozygotes of the ATP2A2 gene compared to carriers of the G allele was shown. But among GG homozygotes, patients with FC II CHF prevailed and participants with FC I CHF were less common than among patients with genotype GA (p=0,041).Conclusion. The association of the AA genotype carriage for the rs1860561 variant of the ATP2A2 gene encoding Ca(2+)-ATPase SERCA2a, with a decrease in the left ventricle ejection fraction in patients with CHF and CAD was revealed. At the same time, among the GG homozygotes, FC I CHF was the least prevalent. There was no association of the rY3766871 variant of the RYR2 gene with CHF severity.

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Gordeuk, Victor R., Xu Zhang, Wei Zhang, Shwu-Fan Ma, Craig Sable, Galina Miasniakova, Adelina Sergueeva et al. « Novel Putative Polymorphism in SERPINC1 Encoding Antithrombin III Is Implicated in Elevated Estimated Systolic Pulmonary Pressure in Patients with Chuvash Polycythemia. » Blood 120, n^o 21 (16 novembre 2012) : 2869. http://dx.doi.org/10.1182/blood.v120.21.2869.2869.

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Abstract Abstract 2869 Chuvash polycythemia (CP) is characterized by homozygosity for the R200W mutation in the von Hippel Lindau gene (VHL). This rare genetic disorder causes elevated levels of hypoxia inducible factor (HIF)-1 and HIF-2 that trigger constitutive hypoxia responses at normoxia. Hypoxia is a recognized cause of pulmonary hypertension. We recently reported that systolic pulmonary artery pressure (SPAP) estimated by echocardiography-determined tricuspid regurgitation velocity (TRV) was elevated in 120 CP patients compared to 31 Chuvash controls (P = 0.005), and that increasing age (P = 0.001), increasing systemic pulse pressure (P = 0.003) and lower serum ferritin concentration (P = 0.009) were independent predictors of higher estimated SPAP in CP patients [Sable et al., 2012]. In this study, we profiled gene expression for 16,642 genes in peripheral blood mononuclear cells (PBMCs) derived from a cohort of 43 CP patients, and measured the TRV for these individuals. Based on a prospectively chosen criterion of TRV ≥2.5 m/sec, 20 patients were classified as having elevated level of estimated SPAP and 23 were normal. Gene expression level between these two SPAP groups appeared to be homogenous. However, we identified 4777 genes at false discovery rate (FDR) <0.05 that exhibit pulse pressure by SPAP group interaction, suggesting a profound difference in pulse pressure regulation between the two SPAP groups. Further analysis of probe level data revealed a potential genetic polymorphism located within exon 7 of SERPINC1, encoding antithrombin III, at a site where a disease-associated SNP has not been reported. The minor allele of this polymorphism, which we designated “B”, was highly enriched in the elevated estimated SPAP group (P=0.0009), and classification based on the putative SERPINC1 genotypes strengthens the interaction effect with pulse pressure. Analysis of the gene expression data for the 43 CP patients with an additive genetic model of SERPINC1 identified 1902 differential genes at FDR <0.05. The 1120 genes up-regulated by the B allele were highly enriched in the Reactome G-protein coupled receptor pathway (Padjusted < 8×10−10). Several genes involved in smooth muscle contraction, regulation of blood pressure, and angiogenesis were up-regulated by the putative B allele, for example, HTR5A (serotonin receptor 5A), TAC3 (tachykinin 3), ADRA1D (adrenergic alpha-1D- receptor), BDKRB1 (bradykinin receptor B1), BDKRB2 (bradykinin receptor B1), EDN2 (endothelin 2), PTGER1 (prostaglandin E receptor 1), PTGIR (prostaglandin I2 receptor), APLNR (apelin receptor), RAMP2 (receptor activity modifying protein 2), MYH6 (myosin heavy chain 6), MYH7 (myosin heavy chain 7), MYL2 (myosin light chain 2), MYLK2 (myosin light chain kinase 2), MYLK3 (myosin light chain kinase 3), ACE (angiotensin I converting enzyme 1), ATP2A1 (ATPase cardiac muscle fast twitch 1), ADCY4 (adenylate cyclase 4), and PRKAA2 (protein kinase AMP-activated alpha 2 catalytic subunit). On the other hand, genes whose malfunction has been associated with familial pulmonary hypertension, including BMPR2 (bone morphogenetic protein receptor, type II), SMAD5 (SMAD family member 5), and ACVR2A (activin A receptor, type IIA), were among the 782 genes down regulated by the B allele. These results suggest that alterations in SERPINC1 may be implicated in the development of elevated SPAP in patients with CP. Antithrombin III deficiency is a potential factor in chronic thromboembolic pulmonary hypertension, but our results suggest that the putative B polymorphism may have effects beyond the coagulation cascade. Whether this is due to the SERPINC1 polymorphism itself or to another locus in linkage disequilibrium will require our future planned studies, beginning with sequencing of SERPINC1 exon 7 and identification of the polymorphism. Disclosures: No relevant conflicts of interest to declare.

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Antunes-Duarte, Sofia, Maria Mendonça-Sanches, Rita Pimenta, Ana Margarida Coutinho, Catarina Silveira, Luís Soares-de-Almeida et Paulo Filipe. « Two Novel ATP2C1 Mutations in Portuguese Patients with Hailey-Hailey Disease ». Journal of the Portuguese Society of Dermatology and Venereology 79, n^o 4 (27 décembre 2021) : 373–76. http://dx.doi.org/10.29021/spdv.79.4.1409.

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Hailey-Hailey disease (HHD) is a rare autosomal dominant acantholytic dermatosis. It is characterized by a recurrent eruption of vesicles, erosions, and scaly erythematous plaques involving intertriginous areas and first occurring after puberty, mostly in the third or fourth decade. In 2000, mutations in the ATP2C1 gene on band 3q22.1, encoding the secretory pathway Ca2+/Mn2+-ATPase protein 1(hSPCA1), have been identified as the cause of HHD. We report the identification of two novel mutations of ATP2C1 gene in two Portuguese patients, which expands the spectrum of ATP2C1 mutations underlying HHD and provides useful information for genetic counseling.

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Nanba, Kazutaka, Andrew X. Chen, Kei Omata, Michelle Vinco, Thomas J. Giordano, Tobias Else, Gary D. Hammer, Scott A. Tomlins et William E. Rainey. « Molecular Heterogeneity in Aldosterone-Producing Adenomas ». Journal of Clinical Endocrinology & ; Metabolism 101, n^o 3 (1 mars 2016) : 999–1007. http://dx.doi.org/10.1210/jc.2015-3239.

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Abstract Context: The use of next-generation sequencing has resulted in the identification of recurrent somatic mutations underlying primary aldosteronism (PA). However, significant gaps remain in our understanding of the relationship between tumor aldosterone synthase (CYP11B2) expression and somatic mutation status. Objective: The objective of the study was to investigate tumor CYP11B2 expression and somatic aldosterone-driver gene mutation heterogeneity. Methods: Fifty-one adrenals from 51 PA patients were studied. Immunohistochemistry for CYP11B2 was performed. Aldosterone-producing adenomas with intratumor CYP11B2 heterogeneity were analyzed for mutation status using targeted next-generation sequencing. DNA was isolated from CYP11B2-positive, CYP11B2-negative, and adjacent normal areas from formalin-fixed, paraffin-embedded sections. Results: Of 51 adrenals, seven (14 %) showed distinct heterogeneity in CYP11B2 by immunohistochemistry, including six adenomas with intratumor heterogeneity and one multinodular hyperplastic adrenal with both CYP11B2-positive and -negative nodules. Of the six adrenocortical adenomas with CYP11B2 heterogeneity, three had aldosterone-regulating mutations (CACNA1D p.F747C, KCNJ5 p.L168R, ATP1A1 p.L104R) only in CYP11B2-positive regions, and one had two different mutations localized to two histologically distinct CYP11B2-positive regions (ATP2B3 p.L424_V425del, KCNJ5 p.G151R). Lastly, one adrenal with multiple CYP11B2-expressing nodules showed different mutations in each (CACNA1D p.F747V and ATP1A1 p.L104R), and no mutations were identified in CYP11B2-negative nodule or adjacent normal adrenal. Conclusions: Adrenal tumors in patients with PA can demonstrate clear heterogeneity in CYP11B2 expression and somatic mutations in driver genes for aldosterone production. These findings suggest that aldosterone-producing adenoma tumorigenesis can occur within preexisting nodules through the acquisition of somatic mutations that drive aldosterone production.

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Shimizu, Noriaki, Noritada Yoshikawa, Tadashi Wada, Hiroshi Handa, Motoaki Sano, Keiichi Fukuda, Makoto Suematsu, Takashi Sawai, Chikao Morimoto et Hirotoshi Hirotoshi. « Tissue- and Context-Dependent Modulation of Hormonal Sensitivity of Glucocorticoid-Responsive Genes by Hexamethylene Bisacetamide-Inducible Protein 1 ». Molecular Endocrinology 22, n^o 12 (1 décembre 2008) : 2609–23. http://dx.doi.org/10.1210/me.2008-0101.

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Abstract Physiological and pharmacological processes mediated by glucocorticoids involve tissue- and context-specific regulation of glucocorticoid-responsive gene expression via glucocorticoid receptor (GR). However, the molecular mechanisms underlying such highly coordinated regulation of glucocorticoid actions remain to be studied. We here addressed this issue using atp1a1 and scnn1a, both of which are up-regulated in response to corticosteroids in human embryonic kidney-derived 293 cells, but resistant in liver-derived HepG2 cells. Hexamethylene bisacetamide-inducible protein 1 (HEXIM1) represses gene expression via, at least, two distinct mechanisms, i.e. positive transcription elongation factor b sequestration and direct interaction with GR, and is relatively high in HepG2 cells compared with 293 cells. Given this, we focused on the role of HEXIM1 in transcriptional regulation of these GR target genes. In HepG2 cells, hormone resistance of atp1a1 and scnn1a was diminished by either knockdown of HEXIM1 or overexpression of GR. Such a positive effect of exogenous expression of GR was counteracted by concomitant overexpression of HEXIM1, indicating the balance between GR and HEXIM1 modulates hormonal sensitivity of these genes. In support of this, the hormone-dependent recruitment of RNA polymerase II onto atp1a1 promoter was in parallel with that of GR. Moreover, we revealed that not positive transcription elongation factor b-suppressing activity but direct interaction with GR of HEXIM1 plays a major role in suppression of promoter recruitment of the receptor and subsequent atp1a1 and scnn1a gene activation. Collectively, we may conclude that HEXIM1 may participate in tissue-selective determination of glucocorticoid sensitivity via direct interaction with GR at least in certain gene sets including atp1a1 and scnn1a.

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ORLOV, SERGEI N., JULIE DUTIL, PAVEL HAMET et ALAN Y. DENG. « Replacement of α1-Na-K-ATPase of Dahl rats by Milan rats lowers blood pressure but does not affect its activity ». Physiological Genomics 7, n^o 2 (21 décembre 2001) : 171–77. http://dx.doi.org/10.1152/physiolgenomics.00059.2001.

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Both linkage and use of congenic strains have shown that a chromosome region near the gene for the Na-K-ATPase α1-subunit ( Atp1a1) contained a quantitative trait locus (QTL) for blood pressure (BP). Currently, two congenic strains, designated S.M5 and S.M6, were made by replacing a segment of the Dahl salt-sensitive SS/Jr (S) rat by the homologous region of the Milan normotensive rat (MNS). In S.M5, the gene for Atp1a1 is from the MNS strain; whereas in S.M6, Atp1a1 is from the S strain. The baseline activity of the α1-Na-K-ATPase and its stoichiometry were evaluated by an assay of ouabain-sensitive inwardly and outwardly directed 86Rb and 22Na fluxes in erythrocytes. The two congenic strains showed a similar BP, but both had a BP lower than that of S rats ( P < 0.0001). Neither the α1-Na-K-ATPase activity nor its stoichiometry was affected by the substitution of the Atp1a1 alleles of S by those of MNS. Thus the BP-lowering effects observed in S.M5 and S.M6 could not be attributed to the α1-Na-K-ATPase activity or its stoichiometry. Atp1a1 is not supported as a candidate to be a BP QTL.

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Wu, Che-Hsiung, Kang-Yung Peng, Daw-Yang Hwang, Yen-Hung Lin, Vin-Cent Wu et Jeff S. Chueh. « Novel Mutations Detection with Next-Generation Sequencing and Its Association with Clinical Outcome in Unilateral Primary Aldosteronism ». Biomedicines 9, n^o 9 (6 septembre 2021) : 1167. http://dx.doi.org/10.3390/biomedicines9091167.

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Somatic mutations have been identified in adrenal tissues of unilateral primary aldosteronism (uPA). The spectrum of somatic mutations in uPAs was investigated using a customized and targeted next-generation sequencing (cNGS) approach. We also assessed whether cNGS or Sanger sequencing-identified mutations have an association with clinical outcomes in uPA. Adrenal tumoral tissues of uPA patients who underwent adrenalectomy were obtained. Conventional somatic mutation hotspots in 240 extracted DNA samples were initially screened using Sanger sequencing. A total of 75 Sanger-negative samples were further investigated by sequencing the entire coding regions of the known aldosterone-driver genes by our cNGS gene panel. Somatic mutations in aldosterone-driver genes were detected in 21 (28%) of these samples (8.8% of all samples), with 9 samples, including mutations in CACNA1D gene (12%), 5 in CACNA1H (6.6%), 3 in ATP2B3 (4%), 2 in CLCN2 (2.6%), 1 in ATP1A1 (1.3%), and 1 in CTNNB1 (1.3%). Via combined cNGS and Sanger sequencing aldosterone-driver gene mutations were detected in altogether 186 of our 240 (77.5%) uPA samples. The complete clinical success rate of patients containing cNGS-identified mutations was higher than those without mutations (odds ratio (OR) = 10.9; p = 0.012). Identification of somatic mutations with cNGS or Sanger sequencing may facilitate the prediction of complete clinical success after adrenalectomy in uPA patients.

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Horecka, Eliska, Cenek Horecky, Lenka Kovarikova, Anna Musilova, Ales Knoll, Sarka Nedomova et Ales Pavlik. « Association between Single Nucleotide Polymorphisms of Atp2B1 Gene and Bone Parameters of Laying Hens ». Avian Biology Research 11, n^o 3 (août 2018) : 178–82. http://dx.doi.org/10.3184/175815618x15269357438898.

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Experiments were performed in 110 ISA Brown egg production hens (Gallus gallus), kept from 15 to 26 weeks of age in enriched (furnished) housing technology. The present objective was to investigate the presence of single nucleotide polymorphisms (SNPs) of the ATP2B1 gene and their effects on calcium homeostasis in laying hens. The plasma membrane calcium-transporting ATPase 1 gene (ATP2B1) in hens is located on chromosome 1, region 43 273 706 – 43 305 815 bp. The ATP2B1 gene has 21 exons, and in this study three were genotyped. In each experimental group of animals, only alleles without deletions in exon 10 and only allele A in exon 12 were found. In exon 8, only genotypes CC/CC, TT/CC and TT/TT were found. These genotypes are associated with femur breaking strength, bone diameter, bone marrow diameter and compact bone thickness. No significant effects of SNPs in exon 8 on bone characteristics were found.

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Korošec, Branka, Damjan Glavač, Metka Volavšek et Metka Ravnik-Glavač. « ATP2A3 gene is involved in cancer susceptibility ». Cancer Genetics and Cytogenetics 188, n^o 2 (janvier 2009) : 88–94. http://dx.doi.org/10.1016/j.cancergencyto.2008.10.007.

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Nakajima, Kazuo, Mizuho Ishiwata, Adam Z. Weitemier, Hirotaka Shoji, Hiromu Monai, Hiroyuki Miyamoto, Kazuhiro Yamakawa, Tsuyoshi Miyakawa, Thomas J. McHugh et Tadafumi Kato. « Brain-specific heterozygous loss-of-function of ATP2A2, endoplasmic reticulum Ca2+ pump responsible for Darier’s disease, causes behavioral abnormalities and a hyper-dopaminergic state ». Human Molecular Genetics 30, n^o 18 (8 juin 2021) : 1762–72. http://dx.doi.org/10.1093/hmg/ddab137.

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Abstract A report of a family of Darier’s disease with mood disorders drew attention when the causative gene was identified as ATP2A2 (or SERCA2), which encodes a Ca2+ pump on the endoplasmic reticulum (ER) membrane and is important for intracellular Ca2+ signaling. Recently, it was found that loss-of-function mutations of ATP2A2 confer a risk of neuropsychiatric disorders including depression, bipolar disorder and schizophrenia. In addition, a genome-wide association study found an association between ATP2A2 and schizophrenia. However, the mechanism of how ATP2A2 contributes to vulnerability to these mental disorders is unknown. Here, we analyzed Atp2a2 heterozygous brain-specific conditional knockout (hetero cKO) mice. The ER membranes prepared from the hetero cKO mouse brain showed decreased Ca2+ uptake activity. In Atp2a2 heterozygous neurons, decays of cytosolic Ca2+ level were slower than control neurons after depolarization. The hetero cKO mice showed altered behavioral responses to novel environments and impairments in fear memory, suggestive of enhanced dopamine signaling. In vivo dialysis demonstrated that extracellular dopamine levels in the NAc were indeed higher in the hetero cKO mice. These results altogether indicate that the haploinsufficiency of Atp2a2 in the brain causes prolonged cytosolic Ca2+ transients, which possibly results in enhanced dopamine signaling, a common feature of mood disorders and schizophrenia. These findings elucidate how ATP2A2 mutations causing a dermatological disease may exert their pleiotropic effects on the brain and confer a risk for mental disorders.

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Nanba, Kazutaka, et William E. Rainey. « GENETICS IN ENDOCRINOLOGY : Impact of race and sex on genetic causes of aldosterone-producing adenomas ». European Journal of Endocrinology 185, n^o 1 (1 juillet 2021) : R1—R11. http://dx.doi.org/10.1530/eje-21-0031.

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Primary aldosteronism (PA) is a common cause of secondary hypertension. Recent technological advances in genetic analysis have provided a better understanding of the molecular pathogenesis of this disease. The application of next-generation sequencing has resulted in the identification of somatic mutations in aldosterone-producing adenoma (APA), a major subtype of PA. Based on the recent findings using a sequencing method that selectively targets the tumor region where aldosterone synthase (CYP11B2) is expressed, the vast majority of APAs appear to harbor a somatic mutation in one of the aldosterone-driver genes, including KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2. Mutations in these genes alter intracellular ion homeostasis and enhance aldosterone production. In a small subset of APAs, somatic activating mutations in the CTNNB1 gene, which encodes β-catenin, have also been detected. Accumulating evidence suggests that race and sex impact the somatic mutation spectrum of APA. Specifically, somatic mutations in the KCNJ5 gene, encoding an inwardly rectifying K+ channel, are common in APAs from Asian populations as well as women regardless of race. Associations between APA histology, genotype, and patient clinical characteristics have also been proposed, suggesting a potential need to consider race and sex for the management of PA patients. Herein, we review recent findings regarding somatic mutations in APA and discuss potential roles of race and sex on the pathophysiology of APA as well as possible clinical implications.

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Wong, Y. W., A. F. Williams, S. F. Kingsmore et M. F. Seldin. « Structure, expression, and genetic linkage of the mouse BCM1 (OX45 or Blast-1) antigen. Evidence for genetic duplication giving rise to the BCM1 region on mouse chromosome 1 and the CD2/LFA3 region on mouse chromosome 3. » Journal of Experimental Medicine 171, n^o 6 (1 juin 1990) : 2115–30. http://dx.doi.org/10.1084/jem.171.6.2115.

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The mouse BCM1 (OX45, Blast-1) antigen has been cDNA cloned and sequenced to provide data supporting the view that BCM1, LFA3, and CD2 constitute a subgroup within the Ig superfamily. Mouse BCM1 is widely expressed on leukocytes and is likely to be anchored to the cell surface by a glycosyl-phosphatidylinositol anchor, as is the case for rat and human BCM1 antigen. Genetic linkage studies by recombination and pulse field analysis showed the BCM1 locus (Bcm-1) to be on distal mouse chromosome 1 and to be linked within 1,600 kb to the locus for an ATPase alpha chain gene (Atpa-3). A similar relationship was established between the human BCM1 locus (BCM1) and ATP1A2, and other markers on chromosome 1q. Conservation of genomic organization within a segment of human chromosome 1q and mouse chromosome 1 was demonstrated. A similar situation is seen in the region of the CD2 and LFA3 genes between mouse chromosome 3 and human chromosome 1p. Furthermore, the CD2/LFA3 genes are linked within 580 kb to Atpa-1/ATP1A1 genes to provide a parallel situation to the linkage between Bcm-1/BCM1 and Atpa-3/ATP1A2 on chromosomes 1 (mouse) and 1q (human). Taken together, the data suggest duplication of a chromosome region including the precursors of the genes for BCM1, CD2, and LFA3, and the ATPase genes to give rise to the linkage groups now observed. The duplicated regions may have stayed together on chromosome 1 in the human (with the insertion of a centromere), while in the mouse, the genetic regions are proposed to have become dispersed in the formation of chromosomes 1 and 3. CD2 and LFA3 are more dissimilar in sequence than BCM1 and LFA3, and if the precursors of the CD2 and LFA3 loci formed before the proposed chromosome segment duplication, then a gene encoding a recognizer molecule for BCM1 may exist in linkage with Bcm-1/BCM1 on chromosome 1 (mouse) and 1q (human).

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Burkard, Christine, Monique H. Verheije, Bart L. Haagmans, Frank J. van Kuppeveld, Peter J. M. Rottier, Berend-Jan Bosch et Cornelis A. M. de Haan. « ATP1A1-Mediated Src Signaling Inhibits Coronavirus Entry into Host Cells ». Journal of Virology 89, n^o 8 (4 février 2015) : 4434–48. http://dx.doi.org/10.1128/jvi.03274-14.

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ABSTRACTIn addition to transporting ions, the multisubunit Na+,K+-ATPase also functions by relaying cardiotonic steroid (CTS)-binding-induced signals into cells. In this study, we analyzed the role of Na+,K+-ATPase and, in particular, of its ATP1A1 α subunit during coronavirus (CoV) infection. As controls, the vesicular stomatitis virus (VSV) and influenza A virus (IAV) were included. Using gene silencing, the ATP1A1 protein was shown to be critical for infection of cells with murine hepatitis virus (MHV), feline infectious peritonitis virus (FIPV), and VSV but not with IAV. Lack of ATP1A1 did not affect virus binding to host cells but resulted in inhibited entry of MHV and VSV. Consistently, nanomolar concentrations of the cardiotonic steroids ouabain and bufalin, which are known not to affect the transport function of Na+,K+-ATPase, inhibited infection of cells with MHV, FIPV, Middle East respiratory syndrome (MERS)-CoV, and VSV, but not IAV, when the compounds were present during virus inoculation. Cardiotonic steroids were shown to inhibit entry of MHV at an early stage, resulting in accumulation of virions close to the cell surface and, as a consequence, in reduced fusion. In agreement with an early block in infection, the inhibition of VSV by CTSs could be bypassed by low-pH shock. Viral RNA replication was not affected when these compounds were added after virus entry. The antiviral effect of ouabain could be relieved by the addition of different Src kinase inhibitors, indicating that Src signaling mediated via ATP1A1 plays a crucial role in the inhibition of CoV and VSV infections.IMPORTANCECoronaviruses (CoVs) are important pathogens of animals and humans, as demonstrated by the recent emergence of new human CoVs of zoonotic origin. Antiviral drugs targeting CoV infections are lacking. In the present study, we show that the ATP1A1 subunit of Na+,K+-ATPase, an ion transporter and signaling transducer, supports CoV infection. Targeting ATP1A1 either by gene silencing or by low concentrations of the ATP1A1-binding cardiotonic steroids ouabain and bufalin resulted in inhibition of infection with murine, feline, and MERS-CoVs at an early entry stage. Infection with the control virus VSV was also inhibited. Src signaling mediated by ATP1A1 was shown to play a crucial role in the inhibition of virus entry by ouabain and bufalin. These results suggest that targeting the Na+,K+-ATPase using cardiotonic steroids, several of which are FDA-approved compounds, may be an attractive therapeutic approach against CoV and VSV infections.

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Yao, Longping, Kai Lin, Zijian Zheng, Sumeyye Koc, Shizhong Zhang, Guohui Lu et Thomas Skutella. « Bioinformatic Analysis of Genetic Factors from Human Blood Samples and Postmortem Brains in Parkinson’s Disease ». Oxidative Medicine and Cellular Longevity 2022 (24 décembre 2022) : 1–18. http://dx.doi.org/10.1155/2022/9235358.

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Parkinson’s disease (PD) is one of the most prevalent neurodegenerative disorders characterized by motor and nonmotor symptoms due to the selective loss of midbrain dopaminergic neurons. Pharmacological and surgical interventions have not been possible to cure PD; however, the cause of neurodegeneration remains unclear. Here, we performed and tested a multitiered bioinformatic analysis using the GEO and Proteinexchange database to investigate the gene expression involved in the pathogenesis of PD. Then we further validated individual differences in gene expression in whole blood samples that we collected in the clinic. We also made an interaction analysis and prediction for these genetic factors. There were in all 1045 genes expressing differently in PD compared with the healthy control group. Protein-protein interaction (PPI) networks showed 10 top hub genes: ACO2, MDH2, SDHA, ATP5A1, UQCRC2, PDHB, SUCLG1, NDUFS3, UQCRC1, and ATP5C1. We validated the ten hub gene expression in clinical PD patients and showed the expression of MDH2 was significantly different compared with healthy control. Besides, we also identified the expression of G6PD, GRID2, RIPK2, CUL4B, BCL6, MRPS31, GPI, and MAP 2 K1 were all significantly increased, and levels of MAPK, ELAVL1, RAB14, KLF9, ARF1, ARFGAP1, ATG7, ABCA7, SFT2D2, E2F2, MAPK7, and UHRF1 were all significantly decreased in PD. Among them, to our knowledge, we presently have the most recent and conclusive evidence that GRID2, RIPK2, CUL4B, E2F2, and ABCA7 are possible PD indicators. We confirmed several genetic factors which may be involved in the pathogenesis of PD. They could be promising markers for discriminating the PD and potential factors that may affect PD development.

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Modyanov, N. N., P. M. Mathews, A. V. Grishin, P. Beguin, A. T. Beggah, B. C. Rossier, J. D. Horisberger et K. Geering. « Human ATP1AL1 gene encodes a ouabain-sensitive H-K-ATPase ». American Journal of Physiology-Cell Physiology 269, n^o 4 (1 octobre 1995) : C992—C997. http://dx.doi.org/10.1152/ajpcell.1995.269.4.c992.

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The cDNA for ATP1AL1, the fifth member of the human Na-K-adenosinetriphosphatase (ATPase)/H-K-ATPase gene family, was recently cloned (A. V. Grishin, V. E. Sverdlov, M. B. Kostina, and N. N. Modyanov. FEBS Lett. 349: 144-150, 1994). The encoded protein (ATP1AL1) has all the primary structural features common to the catalytic alpha-subunit of ion-transporting P-type ATPases and is similar (63-64% identity) to the Na-K-ATPase alpha-subunit isoforms and the gastric H-K-ATPase alpha-subunit. In this study, ATP1AL1 was expressed in Xenopus laevis oocytes in combination with the beta-subunit of rabbit gastric H-K-ATPase. The functional properties of the stable alpha/beta-complex were studied by 86Rb+ uptake and demonstrated that ATP1AL1 is a novel human K(+)-dependent ATPase [apparent half-constant activation/(K1/2) for K+ approximately 375 microM)]. ATP1AL1-mediated inward K+ transport was inhibited by ouabain (inhibition constant approximately 13 microM) and was found to be inhibited by high concentrations of SCH-28080 (approximately 70% at 500 microM). ATP1AL1 expression resulted in the alkalinization of the oocytes' cytoplasm and ouabain-sensitive proton extrusion, as measured with pH-sensitive microelectrodes. These data argue that ATP1AL1 is the catalytic alpha-subunit of a human nongastric P-type ATPase capable of exchanging extracellular potassium for intracellular protons.

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Mózner, Orsolya, Boglárka Zámbó et Balázs Sarkadi. « Modulation of the Human Erythroid Plasma Membrane Calcium Pump (PMCA4b) Expression by Polymorphic Genetic Variants ». Membranes 11, n^o 8 (30 juillet 2021) : 586. http://dx.doi.org/10.3390/membranes11080586.

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In the human ATP2B4 gene, coding for the plasma membrane calcium pump PMCA4b, a minor haplotype results in the decreased expression of this membrane protein in erythroid cells. The presence of this haplotype and the consequently reduced PMCA4b expression have been suggested to affect red blood cell hydration and malaria susceptibility. By using dual-luciferase reporter assays, we have localized the erythroid-specific regulatory region within the haplotype of the ATP2B4 gene, containing predicted GATA1 binding sites that are affected by SNPs in the minor haplotype. Our results show that, in human erythroid cells, the regulation of ATP2B4 gene expression is significantly affected by GATA1 expression, and we document the role of specific SNPs involved in predicted GATA1 binding. Our findings provide a mechanistic explanation at the molecular level for the reduced erythroid-specific PMCA4b expression in carriers of ATP2B4 gene polymorphic variants.

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Kirk, Eric A., Shiva M. Singh et Charles L. Rice. « ATP2A2 rs3026468 does not associate with quadriceps contractile properties and acute muscle potentiation in humans ». Physiological Genomics 51, n^o 1 (1 janvier 2019) : 10–11. http://dx.doi.org/10.1152/physiolgenomics.00085.2018.

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The ATP2A2 gene encodes the SERCA protein required for active calcium reuptake to the sarcoplasmic reticulum in cardiac and slow-twitch skeletal muscle. The ATP2A2 rs3026468 variant has been associated with voluntary strength phenotypes in humans but requires further validation. Here we investigated a homogenous cohort of 80 young, healthy, active Caucasian males who were assessed for maximal isometric strength, voluntary activation, stimulated contractile properties, and muscle potentiation in the quadriceps. A dynamometer was used to record knee extensions, and electrical stimulation was applied to the thigh to elicit a twitch response. DNA was isolated from cheek swabs, and the rs3026468 genotypes were assessed by TaqMan primer quantitative PCR. The results show no association between ATP2A2 rs3026468 variants and muscle strength measures. We conclude there is no effect of the rs3026468 variant in our cohort and that functional influences do not likely contribute to contractile property differences in young healthy men.

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Mömke, S., et O. Distl. « Molecular characterization of the equine ATP2A2 gene ». Cytogenetic and Genome Research 116, n^o 4 (2007) : 256–62. http://dx.doi.org/10.1159/000100409.

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Kondratieva, D. S., S. A. Afanasiev, E. F. Muslimova, E. A. Archakov et R. E. Batalov. « Relationship of the expression of calcium-handling proteins in the sarcoplasmic reticulum with polymorphic variants of their genes and with structural and functional parameters of the heart in patients with atrial fibrillation ». Bulletin of Siberian Medicine 21, n^o 2 (17 juillet 2022) : 74–81. http://dx.doi.org/10.20538/1682-0363-2022-2-74-81.

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Aim. To investigate the relationship between the expression of Ca2+ handling proteins of the sarcoplasmic reticulum, polymorphic variants of their genes, and structural and functional parameters of the heart in patients with atrial fibrillation (AF).Materials and methods. The study included patients with AF. The patients underwent radiofrequency ablation, during which a myocardial biopsy was taken. The patients underwent echocardiography (EchoCG) before surgery. Polymorphic variants rs1860561 of the ATP2A2 gene and rs6684209 and rs7521023 of the CASQ2 gene were determined in the patients by real-time polymerase chain reaction (PCR), and the level of expression of SERCA2a and CASQ2 proteins in the myocardium was detected by immunoblotting.Results. Carriers of the GG genotype at rs1860561 of the ATP2A2 gene and CC genotype at rs6684209 of the CASQ2 gene were characterized by significantly higher expression of the corresponding proteins. Using cluster analysis, we identified groups of patients by the level of SERCA2a and CASQ2 expression: group 1 – patients with low protein content; group 2 – patients with high protein content. According to clinical and anamnestic parameters, the patients in the selected groups were homogeneous. In patients with high SERCA2a levels, the end systolic and diastolic volumes of the left ventricle (LV) were significantly higher than those in patients with low levels of this protein. The rates of early (peak E) and late left ventricular diastolic filling (peak A) were significantly lower in the group with high SERCA2a expression. A comparative analysis of EchoCG data of patients distributed by the level of CASQ2 expression in the myocardium did not reveal significant differences between the groups.Conclusion. The polymorphic variant rs1860561 of the ATP2A2 gene and rs6684209 of the CASQ2 gene can modulate the level of SERCA2a and CASQ2 expression. SERCA2a expression is associated with the functional and structural parameters of the heart in patients with AF.

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Liu, Changyue, et Wei Yue. « The ATP1A2 Mutation Associated with Hemiplegic Migraines : Case Report and Literature Review ». Clinical and Translational Neuroscience 6, n^o 4 (23 novembre 2022) : 25. http://dx.doi.org/10.3390/ctn6040025.

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Familial hemiplegic migraine type 2 is a premonitory subtype of migraine caused by an ATP1A2 gene mutation. It is an autosomal dominant genetic disease. Here, we report a 51-year-old woman who had a migraine attack due to a pathogenic ATP1A2 gene mutation. With frequent attacks, the patient developed complete left hemiplegia, a confusion of consciousness and partial seizures. Magnetic resonance imaging showed extensive angiogenic edema in the right cerebral hemisphere. In this article, we review the latest literature and try to explain the above symptoms in our patient with cortical spreading depression (CSD) and ATP1A2 gene mutations.

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