Статті в журналах: "AP4S1"

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Behne, Robert, Julian Teinert, Miriam Wimmer, Angelica D’Amore, Alexandra K. Davies, Joseph M. Scarrott, Kathrin Eberhardt, et al. "Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking." Human Molecular Genetics 29, no. 2 (January 9, 2020): 320–34. http://dx.doi.org/10.1093/hmg/ddz310.

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Abstract Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3–5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.

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Vill, Katharina, Wolfgang Müller-Felber, Bader Alhaddad, Tim M. Strom, Veronika Teusch, Heike Weigand, Astrid Blaschek, Thomas Meitinger, and Tobias B. Haack. "A homozygous splice variant in AP4S1 mimicking neurodegeneration with brain iron accumulation." Movement Disorders 32, no. 5 (February 2, 2017): 797–99. http://dx.doi.org/10.1002/mds.26922.

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D’Amore, Angelica, Alessandra Tessa, Valentina Naef, Maria Teresa Bassi, Andrea Citterio, Romina Romaniello, Gianluca Fichi, et al. "Loss of ap4s1 in zebrafish leads to neurodevelopmental defects resembling spastic paraplegia 52." Annals of Clinical and Translational Neurology 7, no. 4 (March 25, 2020): 584–89. http://dx.doi.org/10.1002/acn3.51018.

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Carmona, Susana, Clara Marecos, Marta Amorim, Ana C. Ferreira, Carla Conceição, José Brás, Sofia T. Duarte, and Rita Guerreiro. "AP4S1 splice-site mutation in a case of spastic paraplegia type 52 with polymicrogyria." Neurology Genetics 4, no. 5 (September 19, 2018): e273. http://dx.doi.org/10.1212/nxg.0000000000000273.

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McCullough, Carmel G., Szabolcs Szelinger, Newell Belnap, Keri Ramsey, Isabelle Schrauwen, Ana M. Claasen, Leah W. Burke, et al. "Utilizing RNA and outlier analysis to identify an intronic splice‐altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia." Human Mutation 41, no. 2 (November 14, 2019): 412–19. http://dx.doi.org/10.1002/humu.23939.

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6

Hardies, Katia, Patrick May, Tania Djémié, Oana Tarta-Arsene, Tine Deconinck, Dana Craiu, Ingo Helbig, et al. "Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly." Human Molecular Genetics 24, no. 8 (December 30, 2014): 2218–27. http://dx.doi.org/10.1093/hmg/ddu740.

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Klee, Katharina M. C., Andreas R. Janecke, Hasret A. Civan, Štefan Rosipal, Peter Heinz-Erian, Lukas A. Huber, Thomas Müller, and Georg F. Vogel. "AP1S1 missense mutations cause a congenital enteropathy via an epithelial barrier defect." Human Genetics 139, no. 10 (April 18, 2020): 1247–59. http://dx.doi.org/10.1007/s00439-020-02168-w.

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Abstract Congenital diarrheal disorders (CDD) comprise > 50 monogenic entities featuring chronic diarrhea of early-onset, including defects in nutrient and electrolyte absorption, enterocyte polarization, enteroendocrine cell differentiation, and epithelial integrity. Diarrhea is also a predominant symptom in many immunodeficiencies, congenital disorders of glycosylation, and in some defects of the vesicular sorting and transporting machinery. We set out to identify the etiology of an intractable diarrhea in 2 consanguineous families by whole-exome sequencing, and identified two novel AP1S1 mutations, c.269T>C (p.Leu90Pro) and c.346G>A (p.Glu116Lys). AP1S1 encodes the small subunit of the adaptor protein 1 complex (AP-1), which plays roles in clathrin coat-assembly and trafficking between trans-Golgi network, endosomes and the plasma membrane. An AP1S1 knock-out (KO) of a CaCo2 intestinal cell line was generated to characterize intestinal AP1S1 deficiency as well as identified mutations by stable expression in KO background. Morphology and prototype transporter protein distribution were comparable between parental and KO cells. We observed altered localization of tight-junction proteins ZO-1 and claudin 3, decreased transepithelial electrical resistance and an increased dextran permeability of the CaCo2-AP1S1-KO monolayer. In addition, lumen formation in 3D cultures of these cells was abnormal. Re-expression of wild-type AP1S1 in CaCo2-AP1S1-KO cells reverted these abnormalities, while expression of AP1S1 containing either missense mutation did not. Our data indicate that loss of AP1S1 function causes an intestinal epithelial barrier defect, and that AP1S1 mutations can cause a non-syndromic form of congenital diarrhea, whereas 2 reported truncating AP1S1 mutations caused MEDNIK syndrome, characterized by mental retardation, enteropathy, deafness, neuropathy, ichthyosis, and keratodermia.

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8

Hannan, Fadil M., Mark Stevenson, Asha L. Bayliss, Victoria J. Stokes, Michelle Stewart, Kreepa G. Kooblall, Caroline M. Gorvin, et al. "Ap2s1 mutation causes hypercalcaemia in mice and impairs interaction between calcium-sensing receptor and adaptor protein-2." Human Molecular Genetics 30, no. 10 (March 17, 2021): 880–92. http://dx.doi.org/10.1093/hmg/ddab076.

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Abstract Adaptor protein 2 (AP2), a heterotetrameric complex comprising AP2α, AP2β2, AP2μ2 and AP2σ2 subunits, is ubiquitously expressed and involved in endocytosis and trafficking of membrane proteins, such as the calcium-sensing receptor (CaSR), a G-protein coupled receptor that signals via Gα11. Mutations of CaSR, Gα11 and AP2σ2, encoded by AP2S1, cause familial hypocalciuric hypercalcaemia types 1–3 (FHH1–3), respectively. FHH3 patients have heterozygous AP2S1 missense Arg15 mutations (p.Arg15Cys, p.Arg15His or p.Arg15Leu) with hypercalcaemia, which may be marked and symptomatic, and occasional hypophosphataemia and osteomalacia. To further characterize the phenotypic spectrum and calcitropic pathophysiology of FHH3, we used CRISPR/Cas9 genome editing to generate mice harboring the AP2S1 p.Arg15Leu mutation, which causes the most severe FHH3 phenotype. Heterozygous (Ap2s1+/L15) mice were viable, and had marked hypercalcaemia, hypermagnesaemia, hypophosphataemia, and increases in alkaline phosphatase activity and fibroblast growth factor-23. Plasma 1,25-dihydroxyvitamin D was normal, and no alterations in bone mineral density or bone turnover were noted. Homozygous (Ap2s1L15/L15) mice invariably died perinatally. Co-immunoprecipitation studies showed that the AP2S1 p.Arg15Leu mutation impaired protein–protein interactions between AP2σ2 and the other AP2 subunits, and also with the CaSR. Cinacalcet, a CaSR positive allosteric modulator, decreased plasma calcium and parathyroid hormone concentrations in Ap2s1+/L15 mice, but had no effect on the diminished AP2σ2-CaSR interaction in vitro. Thus, our studies have established a mouse model that is representative for FHH3 in humans, and demonstrated that the AP2S1 p.Arg15Leu mutation causes a predominantly calcitropic phenotype, which can be ameliorated by treatment with cinacalcet.

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9

Gavalas, Nikos G., E. Helen Kemp, Kai J. E. Krohn, Edward M. Brown, Philip F. Watson, and Anthony P. Weetman. "The Calcium-Sensing Receptor Is a Target of Autoantibodies in Patients with Autoimmune Polyendocrine Syndrome Type 1." Journal of Clinical Endocrinology & Metabolism 92, no. 6 (June 1, 2007): 2107–14. http://dx.doi.org/10.1210/jc.2006-2466.

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Abstract Context: Autoimmune polyendocrine syndrome type 1 (APS1) is an autosomal recessive disorder caused by mutations in the autoimmune regulator gene. Hypoparathyroidism occurs in 80% of patients with APS1 and has been suggested to result from an autoimmune reaction against the calcium-sensing receptor (CaSR) on parathyroid cells. However, the detection of CaSR antibodies in APS1 remains controversial, with some studies disputing the relevance of the receptor as an autoantigen. Objective: The aim of this study was to analyze a defined set of APS1 patient sera for the presence of CaSR antibodies using different assay systems. Results: APS1 patients and individuals with other autoimmune disorders along with healthy subjects were tested for antibody binding to the CaSR. In an immunoprecipitation assay with the CaSR expressed in human embryonic kidney 293 cells, 12 of 14 (85.7%) APS1 and two of 28 (7.1%) Graves’ disease patients were considered positive for CaSR antibodies. The prevalence of receptor antibodies was significantly greater than that in the cohort of healthy individuals only in the APS1 patient group (P < 0.0001). In a flow cytometry assay, seven of 14 (50.0%) APS1 patient sera showed binding to the extracellular domain of the CaSR. The prevalence of receptor antibodies in the APS1 patient group was significantly greater than that in the group of healthy controls (P = 0.023). No CaSR antibodies could be detected in any patients or controls using a radiobinding assay. Conclusion: The CaSR is an autoantigen in APS1, but detection of antibodies against the receptor appears to be influenced by the assay system used.

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10

Aashiq, Mohamed, Asma Jassim Malallah, Farheen Khan, and Maryam Alsada. "Clinical and Biochemical Features in a Case of Familial Hypocalciuric Hypercalcemia Type 3 with AP2S1 Gene Mutation in Codon Arg15His." Case Reports in Pediatrics 2020 (January 28, 2020): 1–3. http://dx.doi.org/10.1155/2020/7312894.

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Familial hypocalciuric hypercalcemia (FHH) is usually a benign condition divided into three types. FHH-3 occurs in about 20% of the cases and is caused due to missense mutations in AP2S1 (adaptor-related protein complex 2 subunit sigma 1) involving the codon Arg15 (p.R15). We report a case of FHH-3 with a heterozygous mutation in the AP2S1 gene on chr19_47349359 C>T, c.44G>A, p.Arg15His. There are a handful of reports describing the clinical features in patients diagnosed with FHH-3. Herein, we describe the laboratory and clinical features associated with a case of FHH-3 with mutation in the Arg15His codon of the AP2S1 gene.

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INGRAM, Stephen W., Stephen T. SAFRANY, and Larry D. BARNES. "Disruption and overexpression of the Schizosaccharomyces pombe aps1 gene, and effects on growth rate, morphology and intracellular diadenosine 5′,5'-P1,P5-pentaphosphate and diphosphoinositol polyphosphate concentrations." Biochemical Journal 369, no. 3 (February 1, 2003): 519–28. http://dx.doi.org/10.1042/bj20020733.

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Schizosaccharomyces pombe Aps1 is an enzyme that degrades both diadenosine oligophosphates (ApnA, n = 5 or 6) and diphosphoinositol polyphosphates {diphosphoinositol pentakisphosphate (PP-InsP5) and bisdiphosphoinositol tetrakisphosphate ([PP]2-InsP4)} in vitro. The in vivo substrates of Aps1 are unknown. We report here the identification of Ap5A, PP-InsP5, [PP]2-InsP4 and a novel diphosphoinositol polyphosphate ([PP]x-InsPx) in S. pombe using HPLC methods. Ap5A was present at 0.06pmol/mg of protein (approx. 4nM). PP-InsP5, [PP]x-InsPx and [PP]2-InsP4 were present at 15pmol/mg (approx. 1.1μM), 15pmol/mg (approx. 1.1μM) and 30pmol/mg (approx. 2.2μM) respectively, while the intracellular concentration of InsP6 was 0.5nmol/mg of protein (approx. 36μM). Disruption of aps1 resulted in a 52% decrease in Ap6A hydrolase activity in vitro, no detectable change in the intracellular Ap5A concentration, and 3-fold increased intracellular concentrations of PP-InsP5 and [PP]x-InsPx. Disruption of aps1 resulted in no detectable change in morphology or growth rate in minimal or rich media at 30°C. Overexpression of aps1 via two different plasmids that resulted in 60% and 6-fold increases above wild-type enzymic activity in vitro caused no detectable changes in the intracellular concentrations of [PP]2-InsP4, [PP]x-InsPx or PP-InsP5, but paradoxical increases of approx. 2.5- and 55-fold respectively in the intracellular Ap5A concentration. Overexpression of aps1 also resulted in a reduced growth rate and in morphological changes, including swollen, rounded and multiseptate cells. No phenotypic changes or changes in intracellular Ap5A occurred upon overexpression of aps1E93Q, which encodes a mutated Aps1 lacking significant enzymic activity. We conclude that Aps1 degrades PP-InsP5 and [PP]x-InsPxin vivo.

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12

В.А., Кадникова,, Руденская, Г.Е., Шатохина, О.Л., Гусева, Д.М., and Рыжкова, О.П. "Spastic paraplegia type 47 in Russian patients." Nauchno-prakticheskii zhurnal «Medicinskaia genetika, no. 9 (September 30, 2022): 56–60. http://dx.doi.org/10.25557/2073-7998.2022.09.56-60.

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Гомозиготные и компаунд-гетерозиготные мутации в гене AP4B1 приводят к спастической параплегии SPG47. Для неё характерны микроцефалия, гипоплазия мозолистого тела, неонатальная мышечная гипотония, сменяющаяся спастичностью, а также тяжелая умственная отсталость. Повторяющийся вариант c.1160_1161del был выявлен у шести пациентов из неродственных неинбредных семей. Был проведен анализ гаплотипов гена AP4B1 у четырех из шести больных на хромосомах с этой мутацией, в результате чего не выявлено единственного гаплотипа, сцепленного с данным вариантом. Таким образом, он может быть, как горячей точкой, так и распространиться в результате эффекта основателя. The reason of SPG47 is homozygous and compound-heterozygous mutations in AP4B1 gene. SPG47 is characterized by microcephaly, corpus callosum hypoplasia, neonatal muscular hypotension, followed by spasticity and severe mental retardation. Variant c.1160_1161del was identified in six patients from unrelated, non-consanguineous families. Was performed haplotype analysis AP4B1 gene for four from six patients on chromosomes with this variant. As a result, there wasn’t found the only haplotype linked to this variant. Therefore, this variant can be a “hot spot” mutation, or could have spread as a result the founder effect.

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Kemp, E. Helen, Nikos G. Gavalas, Kai J. E. Krohn, Edward M. Brown, Philip F. Watson, and Anthony P. Weetman. "Activating Autoantibodies against the Calcium-Sensing Receptor Detected in Two Patients with Autoimmune Polyendocrine Syndrome Type 1." Journal of Clinical Endocrinology & Metabolism 94, no. 12 (December 1, 2009): 4749–56. http://dx.doi.org/10.1210/jc.2009-1080.

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Context: Autoimmune polyendocrine syndrome type 1 (APS1) is an autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. Hypoparathyroidism occurs in 80% of patients with APS1 and has been suggested to result from an autoimmune reaction against the calcium-sensing receptor (CaSR) in parathyroid cells. Anti-CaSR binding antibodies have previously been detected in patients with APS1. Objective: The aim of this study was to determine whether anti-CaSR antibodies present in APS1 patients could modulate the response of the CaSR to stimulation by Ca2+. Results: The results indicated that two of the 14 APS1 patients included in the study had anti-CaSR antibodies that stimulated the receptor. These antibodies were detected by their ability to increase both Ca2+-dependent extracellular signal-regulated kinase phosphorylation and inositol phosphate accumulation in human embryonic kidney 293 cells expressing the CaSR. Conclusion: An important implication of the present results is that although the majority of APS1 patients do not have CaSR-stimulating antibodies, there may be a small but substantial minority of patients in whom the hypoparathyroid state is the result of functional suppression of the parathyroid glands rather than their irreversible destruction.

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Hovden, Silje, Lars Rejnmark, Søren A. Ladefoged, and Peter H. Nissen. "AP2S1 and GNA11 mutations – not a common cause of familial hypocalciuric hypercalcemia." European Journal of Endocrinology 176, no. 2 (February 2017): 177–85. http://dx.doi.org/10.1530/eje-16-0842.

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Objective Familial hypocalciuric hypercalcemia (FHH) type 1 is caused by mutations in the gene encoding the calcium-sensing receptor (CASR). Recently, mutations affecting codon 15 in the gene AP2S1 have been shown to cause FHH type 3 in up to 26% of CASR-negative FHH patients. Similarly, mutations in the gene GNA11 have been shown to cause FHH type 2. We hypothesized that mutations in AP2S1 and GNA11 are causative in Danish patients with suspected FHH and that these mutations are not found in patients with primary hyperparathyroidism (PHPT), which is the main differential diagnostic disorder. Design Cross-sectional study. Methods We identified patients with unexplained hyperparathyroid hypercalcemia and a control group of verified PHPT patients through review of 421 patients tested for CASR mutations in the period 2006–2014. DNA sequencing of all amino acid coding exons including intron–exon boundaries in AP2S1 and GNA11 was performed. Results In 33 CASR-negative patients with suspected FHH, we found two (~6%) with a mutation in AP2S1 (p.Arg15Leu and p.Arg15His). Family screening confirmed the genotype–phenotype correlations. We did not identify any pathogenic mutations in GNA11. No pathogenic mutations were found in the PHPT control group. Conclusions We suggest that the best diagnostic approach to hyperparathyroid hypercalcemic patients suspected to have FHH is to screen the CASR and AP2S1 codon 15 for mutations. If the results are negative and there is still suspicion of an inherited condition (i.e. family history), then GNA11 should be examined.

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Deenick, Elissa, Anthony Lau, Tina Nguyen, Julia Bier, Robert Brink та Stuart Tangye. "Analysing the cellular mechanisms underlying activated PI3K δ Syndrome (APDS) reveals differences between APDS1 and APDS2". Journal of Immunology 208, № 1_Supplement (1 травня 2022): 159.15. http://dx.doi.org/10.4049/jimmunol.208.supp.159.15.

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Abstract APDS is a primary immunodeficiency condition caused by heterozygous gain-of-function mutations in PIK3CD (APDS1), which encodes the leukocyte-restricted p110-δ catalytic subunit of phosphoinositide 3-kinase (PI3K) or heterozygous loss-of-function mutations in PIK3R1 (APDS2), which encodes the regulatory subunit of PI3K. PI3K is activated downstream of many receptors expressed by lymphocytes and plays important roles in their activation and differentiation. The increased PI3K activity in cells from APDS patients leads to multiple immune manifestations including lymphoproliferation, respiratory tract infections, Th2-related pathologies, impaired Ab responses and autoimmunity. We previously dissected the cellular defects that lead to disease in APDS1 by studying patient cells and our novel mouse model. This revealed changes in lymphocytes including increased memory T cells, defective Tfh function, decreased isotype switching and a break in B cell tolerance and production of autoantibodies. We have now generated a mouse model of APDS2 (Pik3r1E11SpD) and use this together with studies of patients’ cells to determine whether increased PI3K signalling due to loss of regulatory function causes the same cellular dysregulation. While we observed many of the same changes previously observed in APDS1, including altered cytokine production and decreased isotype switching, we also identified multiple differences in the cellular phenotype in APDS2 compared to APDS1. Together, these studies reveal that although APDS1 and 2 both cause increased PI3K signalling and result in similar clinical phenotypes, there are distinctions between how these two types of mutations affect cellular function. Supported by grants from the NHMRC and an AAI Careers in Immunology Fellowship

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Brozzetti, Annalisa, Stefania Marzotti, Daria La Torre, Maria Luisa Bacosi, Silvia Morelli, Vittorio Bini, Bruno Ambrosi, et al. "Autoantibody responses in autoimmune ovarian insufficiency and in Addison's disease are IgG1 dominated and suggest a predominant, but not exclusive, Th1 type of response." European Journal of Endocrinology 163, no. 2 (August 2010): 309–17. http://dx.doi.org/10.1530/eje-10-0257.

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ObjectiveSteroid-producing cell autoantibodies (SCAs) directed against 21-hydroxylase autoantibodies (21OHAbs), 17α-hydroxylase autoantibodies (17OHAb), and cholesterol side-chain cleavage enzyme (side-chain cleavage autoantibodies, P450sccAb) characterize autoimmune primary ovarian insufficiency (SCA-POI). The aim of the study was to analyze IgG subclass specificity of autoantibodies related to adrenal and ovarian autoimmunity.DesignWe studied 29 women with SCA-POI, 30 women with autoimmune Addison's disease (AAD) without POI, and 14 patients with autoimmune polyendocrine syndrome type 1 (APS1). 21OHAb isotypes were also analyzed in 14 subjects with preclinical AAD. Samples from 30 healthy women served as control group to determine the upper level of normality in the isotype assays.MethodsImmunoradiometric assays with IgG subclass-specific secondary antibodies.ResultsIn 21OHAb-positive sera, IgG1 isotype was detected in 90% SCA-POI and non-POI AAD sera and 67% APS1 patients. IgG1 isotype was found in 69% 17OHAb-positive SCA-POI and 100% 17OHAb-positive APS1 sera, and in 60% P450sccAb-positive SCA-POI and 80% P450sccAb-positive APS1 sera. For 21OHAb, IgG4 isotype was detected in 17% SCA-POI, 7% non-POI AAD, and 8% APS1 sera. None of the 17OHAb-positive sera was positive for IgG4. In P450sccAb-positive sera, 15% POI and 20% APS1 sera were positive for IgG4. Two 21OHAb-positive SCA-POI (7%), one 21OHAb-positive AAD (3%), three P450sccAb-positive SCA-POI (15%), and two P450sccAb-positive APS1 (20%) sera were positive for IgG4, in the absence of IgG1. All preclinical AAD sera resulted as positive for IgG1-21OHAb, but not for IgG4-21OHAb.ConclusionsThe autoantibody responses in POI and AAD are IgG1 dominated, which suggests a predominant Th1 response. Selective IgG4 isotype specificity identified a small subset of patients with Th2-oriented response.

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Wong, Felix Chi Kin, Wai Sheung Wong, Jeffrey Sung Shing Kwok, Teresa Kam Chi Tsui, Kam Piu Lau, Michael Ho Ming Chan, and Yuet Ping Yuen. "A Hong Kong Chinese kindred with familial hypocalciuric hypercalcaemia caused by AP2S1 mutation." F1000Research 8 (September 9, 2019): 1612. http://dx.doi.org/10.12688/f1000research.20344.1.

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Familial hypocalciuric hypercalcaemia (FHH) is a genetic disorder of altered calcium homeostasis. Mutations in the CASR, GNA11 and AP2S1 genes have been reported to cause FHH. We report a Hong Kong Chinese kindred with FHH type 3 (FHH3) caused by mutations in AP2S1. The proband, a 51-year-old woman with hypercalcaemia, was initially diagnosed to have primary hyperparathyroidism but repeated parathyroidectomy failed to normalize her plasma calcium concentrations. Later, FHH was suspected and yet no mutations were identified in the CASR gene which causes FHH type 1 (FHH1), the most common form of FHH. Genetic testing of AP2S1 revealed a heterozygous c.43C>T (p.Arg15Cys) mutation, confirming the diagnosis of FHH3. The elder brother and niece of the proband, who both have hypercalcaemia, were found to harbour the same mutation. To our knowledge, this is the first Chinese kindred of FHH3 reported in the English literature.

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Roubertie, Agathe, Nelson Hieu, Charles-Joris Roux, Nicolas Leboucq, Gael Manes, Majida Charif, Bernard Echenne, et al. "AP4 deficiency." Neurology Genetics 4, no. 1 (January 24, 2018): e217. http://dx.doi.org/10.1212/nxg.0000000000000217.

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ObjectiveTo describe the clinico-radiological phenotype of 3 patients harboring a homozygous novel AP4M1 pathogenic mutation.MethodsThe 3 patients from an inbred family who exhibited early-onset developmental delay, tetraparesis, juvenile motor function deterioration, and intellectual deficiency were investigated by magnetic brain imaging using T1-weighted, T2-weighted, T2*-weighted, fluid-attenuated inversion recovery, susceptibility weighted imaging (SWI) sequences. Whole-exome sequencing was performed on the 3 patients.ResultsIn the 3 patients, brain imaging identified the same pattern of bilateral SWI hyposignal of the globus pallidus, concordant with iron accumulation. A novel homozygous nonsense mutation was identified in AP4M1, segregating with the disease and leading to truncation of half of the adap domain of the protein.ConclusionsOur results suggest that AP4M1 represents a new candidate gene that should be considered in the neurodegeneration with brain iron accumulation (NBIA) spectrum of disorders and highlight the intersections between hereditary spastic paraplegia and NBIA clinical presentations.

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Abi warde, M. T., A. De St Martin, R. Touraine, F. Ramond, and J. Chelly. "AP4M1 mutations in patients with epilepsy." European Journal of Paediatric Neurology 21 (June 2017): e105. http://dx.doi.org/10.1016/j.ejpn.2017.04.758.

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20

Zaidi, Ghazala, Vijayalakshmi Bhatia, Saroj K. Sahoo, Aditya Narayan Sarangi, Niharika Bharti, Li Zhang, Liping Yu, et al. "Autoimmune polyendocrine syndrome type 1 in an Indian cohort: a longitudinal study." Endocrine Connections 6, no. 5 (July 2017): 289–96. http://dx.doi.org/10.1530/ec-17-0022.

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Objective Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder characterized by progressive organ-specific autoimmunity. There is scant information on APS1 in ethnic groups other than European Caucasians. We studied clinical aspects and autoimmune regulator (AIRE) gene mutations in a cohort of Indian APS1 patients. Design Twenty-three patients (19 families) from six referral centres in India, diagnosed between 1996 and 2016, were followed for [median (range)] 4 (0.2–19) years. Methods Clinical features, mortality, organ-specific autoantibodies and AIRE gene mutations were studied. Results Patients varied widely in their age of presentation [3.5 (0.1–17) years] and number of clinical manifestations [5 (2–11)]. Despite genetic heterogeneity, the frequencies of the major APS1 components (mucocutaneous candidiasis: 96%; hypoparathyroidism: 91%; primary adrenal insufficiency: 55%) were similar to reports in European series. In contrast, primary hypothyroidism (23%) occurred more frequently and at an early age, while kerato-conjunctivitis, urticarial rash and autoimmune hepatitis were uncommon (9% each). Six (26%) patients died at a young age [5.8 (3–23) years] due to septicaemia, hepatic failure and adrenal/hypocalcaemic crisis from non-compliance/unexplained cause. Interferon-α and/or interleukin-22 antibodies were elevated in all 19 patients tested, including an asymptomatic infant. Eleven AIRE mutations were detected, the most common being p.C322fsX372 (haplotype frequency 37%). Four mutations were novel, while six others were previously described in European Caucasians. Conclusions Indian APS1 patients exhibited considerable genetic heterogeneity and had highly variable clinical features. While the frequency of major manifestations was similar to that of European Caucasians, other features showed significant differences. A high mortality at a young age was observed.

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King, Barbara J. "Towards an ethnography of African great apes1." Social Anthropology 12, no. 2 (January 19, 2007): 195–207. http://dx.doi.org/10.1111/j.1469-8676.2004.tb00101.x.

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Wallace, I. R., V. McConnell, P. M. Bell, and J. R. Lindsay. "Challenges in Management of Primary Hypoparathyroidism Associated with Autoimmune Polyglandular Syndrome Type 1." Case Reports in Endocrinology 2011 (2011): 1–3. http://dx.doi.org/10.1155/2011/281758.

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We report a case of autoimmune polyglandular syndrome type 1 (APS1) complicated by severe vascular insufficiency due to diffuse vascular calcification. APS1 is characterised clinically by multiple autoimmune conditions and development of at least two components of the triad of mucocutaneous candidiasis, hypoparathyroidism, and autoimmune adrenal insufficiency. We highlight the problems in current serum calcium monitoring methods and suggest that fluctuations in serum calcium concentrations due to difficulties treating hypoparathyroidism may have contributed to the vascular calcification seen in this case.

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Eliyahu, Erez, Ido Rog, Dangoor Inbal, and Avihai Danon. "ACHT4-driven oxidation of APS1 attenuates starch synthesis under low light intensity in Arabidopsis plants." Proceedings of the National Academy of Sciences 112, no. 41 (September 30, 2015): 12876–81. http://dx.doi.org/10.1073/pnas.1515513112.

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The regulatory mechanisms that use signals of low levels of reactive oxygen species (ROS) could be obscured by ROS produced under stress and thus are better investigated under homeostatic conditions. Previous studies showed that the chloroplastic atypical thioredoxin ACHT1 is oxidized by 2-Cys peroxiredoxin (2-Cys Prx) in Arabidopsis plants illuminated with growth light and in turn transmits a disulfide-based signal via yet unknown target proteins in a feedback regulation of photosynthesis. Here, we studied the role of a second chloroplastic paralog, ACHT4, in plants subjected to low light conditions. Likewise, ACHT4 reacted in planta with 2-Cys Prx, indicating that it is oxidized by a similar disulfide exchange reaction. ACHT4 further reacted uniquely with the small subunit (APS1) of ADP-glucose pyrophosphorylase (AGPase), the first committed enzyme of the starch synthesis pathway, suggesting that it transfers the disulfides it receives from 2-Cys Prx to APS1 and turns off AGPase. In accordance, ACHT4 participated in an oxidative signal that quenched AGPase activity during the diurnal transition from day to night, and also in an attenuating oxidative signal of AGPase in a dynamic response to small fluctuations in light intensity during the day. Increasing the level of expressed ACHT4 or of ACHT4ΔC, a C terminus-deleted form that does not react with APS1, correspondingly decreased or increased the level of reduced APS1 and decreased or increased transitory starch content. These findings imply that oxidative control mechanisms act in concert with reductive signals to fine tune starch synthesis during daily homeostatic conditions.

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Dornan, Gillian L., Braden D. Siempelkamp, Meredith L. Jenkins, Oscar Vadas, Carrie L. Lucas та John E. Burke. "Conformational disruption of PI3Kδ regulation by immunodeficiency mutations inPIK3CDandPIK3R1". Proceedings of the National Academy of Sciences 114, № 8 (6 лютого 2017): 1982–87. http://dx.doi.org/10.1073/pnas.1617244114.

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Activated PI3K Delta Syndrome (APDS) is a primary immunodeficiency disease caused by activating mutations in either the leukocyte-restricted p110δ catalytic (PIK3CD) subunit or the ubiquitously expressed p85α regulatory (PIK3R1) subunit of class IA phosphoinositide 3-kinases (PI3Ks). There are two classes of APDS: APDS1 that arises from p110δ mutations that are analogous to oncogenic mutations found in the broadly expressed p110α subunit and APDS2 that occurs from a splice mutation resulting in p85α with a central deletion (Δ434–475). As p85 regulatory subunits associate with and inhibit all class IA catalytic subunits, APDS2 mutations are expected to similarly activate p110α, β, and δ, yet APDS2 largely phenocopies APDS1 without dramatic effects outside the immune system. We have examined the molecular mechanism of activation of both classes of APDS mutations using a combination of biochemical assays and hydrogen–deuterium exchange mass spectrometry. Intriguingly, we find that an APDS2 mutation in p85α leads to substantial basal activation of p110δ (>300-fold) and disrupts inhibitory interactions from the nSH2, iSH2, and cSH2 domains of p85, whereas p110α is only minimally basally activated (∼2-fold) when associated with mutated p85α. APDS1 mutations in p110δ (N334K, E525K, E1021K) mimic the activation mechanisms previously discovered for oncogenic mutations in p110α. All APDS mutations were potently inhibited by the Food and Drug Administration-approved p110δ inhibitor idelalisib. Our results define the molecular basis of howPIK3CDandPIK3R1mutations result in APDS and reveal a potential path to treatment for all APDS patients.

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Howles, Sarah A., Fadil M. Hannan, Valerie N. Babinsky, Angela Rogers, Caroline M. Gorvin, Nigel Rust, Tristan Richardson, Malachi J. McKenna, M. Andrew Nesbit, and Rajesh V. Thakker. "Cinacalcet for Symptomatic Hypercalcemia Caused by AP2S1 Mutations." New England Journal of Medicine 374, no. 14 (April 7, 2016): 1396–98. http://dx.doi.org/10.1056/nejmc1511646.

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Kerut, Sarah, Karthik Reddy Kovvuru, Licy Yanes-Cardozo, and Vishnu Vardhan Garla. "Familial hypocalciuric hypercalcaemia type 3: AP2S1 missense mutation." BMJ Case Reports 13, no. 11 (November 2020): e236631. http://dx.doi.org/10.1136/bcr-2020-236631.

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A 45-year-old man was referred to endocrine for the evaluation of hypercalcaemia. The calcium was elevated, vitamin D was low with a normal parathyroid hormone. Dual-energy X-ray absorptiometry scan revealed osteoporosis at the lumbar spine and femoral neck. A 24-hour urine collection revealed low urinary calcium, which was believed to be secondary to vitamin D deficiency. A diagnosis of primary hyperparathyroidism was made. The patient underwent a four-gland parathyroid exploration surgery in which three of his parathyroid glands were removed. The pathology was consistent with benign parathyroid tissue. Post surgery, the patient had persistently elevated calcium levels. He was then started on bisphosphonate and cinacalcet for osteoporosis and hypercalcaemia, respectively. Genetic analysis of familial hypocalciuric hypercalcaemia (FHH) showed a p.arg15cys mutation in the AP2S1 gene, confirming the diagnosis of FHH type 3.

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Ebrahimi‐Fakhari, Darius, Chi Cheng, Kira Dies, Amelia Diplock, Danielle B. Pier, Conor S. Ryan, Brendan C. Lanpher, et al. "Clinical and genetic characterization of AP4B1 ‐associated SPG47." American Journal of Medical Genetics Part A 176, no. 2 (November 28, 2017): 311–18. http://dx.doi.org/10.1002/ajmg.a.38561.

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Brozzetti, Annalisa, Mohammad Alimohammadi, Silvia Morelli, Viviana Minarelli, Åsa Hallgren, Roberta Giordano, Annamaria De Bellis, Roberto Perniola, Olle Kämpe, and Alberto Falorni. "Autoantibody Response Against NALP5/MATER in Primary Ovarian Insufficiency and in Autoimmune Addison's Disease." Journal of Clinical Endocrinology & Metabolism 100, no. 5 (May 1, 2015): 1941–48. http://dx.doi.org/10.1210/jc.2014-3571.

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Abstract Context: NACHT leucine-rich-repeat protein 5 (NALP5)/maternal antigen that embryo requires (MATER) is an autoantigen in hypoparathyroidism associated with autoimmune polyendocrine syndrome type 1 (APS1) but is also expressed in the ovary. Mater is an autoantigen in experimental autoimmune oophoritis. Objectives: The objectives of the study were to determine the frequency of NALP5/MATER autoantibodies (NALP5/MATER-Ab) in women with premature ovarian insufficiency (POI) and in patients with autoimmune Addison's disease (AAD) and to evaluate whether inhibin chains are a target for autoantibodies in POI. Methods: Autoantibodies against NALP5/MATER and inhibin chains-α and -βA were determined by radiobinding assays in 172 patients with AAD without clinical signs of gonadal insufficiency, 41 women with both AAD and autoimmune POI [steroidogenic cell autoimmune POI (SCA-POI)], 119 women with idiopathic POI, 19 patients with APS1, and 211 healthy control subjects. Results: NALP5/MATER-Ab were detected in 11 of 19 (58%) sera from APS1 patients, 12 of 172 (7%) AAD sera, 5 of 41 (12%) SCA-POI sera, 0 of 119 idiopathic POI sera and 1 of 211 healthy control sera (P < .001). None of 160 POI sera, including 41 sera from women with SCA-POI and 119 women with idiopathic POI, and none of 211 healthy control sera were positive for inhibin chain-α/βA autoantibodies. Conclusions: NALP5/MATER-Ab are associated with hypoparathyroidism in APS1 but are present also in patients with AAD and in women with SCA-POI without hypoparathyroidism. Inhibin chains do not appear to be likely candidate targets of autoantibodies in human POI.

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Kiseleva, T. A., F. V. Valeeva, D. L. Ekimovskaya, M. A. Makarov, and R. T. Habibullina. "Autoimmune polyglandular syndrome type 1." Medical Herald of the South of Russia 13, no. 2 (June 29, 2022): 168–71. http://dx.doi.org/10.21886/2219-8075-2022-13-2-168-171.

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Type 1 autoimmune polyglandular syndrome (APS1) is a rare disease, with an unknown prevalence in the Russian population. Due to the low awareness of doctors, it takes more time to make the accurate diagnosis and provide correct medical care. This article describes classical features of APS1 and a clinical case of a patient, who did not have one of the most common first manifestation of the disease - mucocutaneous candidiasis. Hypocalcemia was detected much later than the first clinical manifestations in the form of generalized seizures occurred. Patient also suffers from tapetoretinal abiotrophy, he completely lost vision in childhood which made it difficult for the doctor and patient to interact in the treatment of the disease.

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Elsheikh, Sahar A., Henry M. Blunk, and Scott Wilhelm. "Clinical Presentation and Management Approach in a Case of Familial Hypocalciuric Hypercalcemia Type 3 Due to APS21 Gene Mutation." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A188. http://dx.doi.org/10.1210/jendso/bvab048.381.

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Abstract Familial hypocalciuric hypercalcemia (FHH) is a genetic disorder caused by dysfunctional calcium homeostasis. Thus far, three types of FHH are known to be caused by mutations inCASR (FHH1), GNA11 (FHH2), and AP2S1 (FHH3). The patient in this case report is a 36-year old male that initially presented for a second opinion after being diagnosed with Primary Hyperparathyroidism(PHPT) with subsequent parathyroidectomy done at another institute, and developed recurrent symptomatic hypercalcemia. Prior to considering this patient for further surgical options, he underwent genetic testing, which revealed he had c.43C>T (p.Arg15Cys) mutation in the AP2S1 gene diagnostic of Familial Hypocalciuric Hypercalcemia Type 3 (FHH3). The patient’s father and sister also have hypercalcemia, and have been offered genetic testing. There have been cases reported of patients with FHH3 that have symptomatic hypercalcemia and that have associated cognitive issues. Many patients with FHH can be misdiagnosed and may undergo unnecessary parathyroidectomy. This case report further elucidates the need to raise awareness of FHH.

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Takahashi, Naohiko, and Tetsunori Saikawa. "Mechanisms of Supraventricular Tachycardia." Journal of Arrhythmia 27, Supplement (2011): AP4_1. http://dx.doi.org/10.4020/jhrs.27.ap4_1.

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Nesbit, M. Andrew, Fadil M. Hannan, Sarah A. Howles, Anita A. C. Reed, Treena Cranston, Clare E. Thakker, Lorna Gregory, et al. "Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3." Nature Genetics 45, no. 1 (December 9, 2012): 93–97. http://dx.doi.org/10.1038/ng.2492.

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Mbaeyi-Nwaoha, Ifeoma Elizabeth, Ebere Ani, and Ngozi Chioma Okoronkwo. "Toxicity of Soursop Leaf Powder and Its Relevance in Determining The Micronutrient Status in Formulated Complementary Food." Journal of Life and Bio Sciences Research 2, no. 01 (March 19, 2021): 19–25. http://dx.doi.org/10.38094/jlbsr20124.

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Complementary food was produced from blends of hungry rice (A), pigeon pea (P) and soursop leaves (S). The raw materials were washed with portable water, dried at room temperature, milled with hammer mill, fermented for 24 hours at 28 ± 2 °C (28 ± 2 °C), oven-dried at 50 °C for 12 hours, remilled, sieved to 1 mm pore size and packaged in polyethylene bags for further analysis. The samples were in the ratio of 70:30:0 (sample APS), 65:30:5 (sample APS1), 60:30:10 (sample APS2) and 55:30:15 (sample APS3). Toxicity test for lethal dose (LD50) was carried out on the soursop leaves. Bioassay was carried out with male albino rats for 28 days including acclimatization period of 7 days. Feed intake and weight gain of experimental rats were recorded daily and weekly. Blood serum was collected before and after feeding trials for analyzing bioavailability of the selected micronutrients. The data were subjected to one-way analysis of variance. Means were separated using the Duncan’s multiple range test and significance was accepted at probability level of 0.05 %. The toxicity test (LD50) indicated safety of soursop leaf as an infusion (oral administration) at lower doses of 10-1000 mg/kg body weight of rats. The bioassay revealed that food intake was significantly (p < 0.05) different among the samples in the first, second and third week. Rats that ate normal rat chow had the highest food intake while the rats that ate APS3 had the lowest food intake. Weight gain was highest in rats that ate rat chow while it was lowest in the rat that ate APS3. Bioavailability of selected micronutrient revealed that calcium content had the highest bioavailability in rats fed with rat chow and lowest in AP. Sample of APS1 had the highest iron bioavailability (47.83 %) among the fortified samples and the rat chow. Zinc had the highest bioavailability (52.86 %) in APS1. The work revealed that selected vitamins were most available in APS2 and the selected minerals were most available in sample APS1.

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Santra, Hiran Kanti, Santanu Maity, and Debdulal Banerjee. "Production of Bioactive Compounds with Broad Spectrum Bactericidal Action, Bio-Film Inhibition and Antilarval Potential by the Secondary Metabolites of the Endophytic Fungus Cochliobolus sp. APS1 Isolated from the Indian Medicinal Herb Andrographis paniculata." Molecules 27, no. 5 (February 22, 2022): 1459. http://dx.doi.org/10.3390/molecules27051459.

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Endophytes, being the co-evolution partners of green host plants, are factories of pharmaceutically valuable novel natural products. Cochliobolus sp. APS1, an endophyte of Andrographis paniculata (Green Chiretta), produces a plethora of natural bioactive compounds and the multipotent alkaloid Aziridine, 1-(2-aminoethyl)-, is the prime one among them. The isolate exhibited antibacterial, anti-biofilm, and antilarval potency. The MIC and MBC values of the ethyl-acetate culture extract ranged from 15.62 to 250 µg/mL against ten pathogenic microorganisms (including MRSA and VRSA). Killing kinetics data along with the leakage of macromolecules into the extracellular environment supports the cidal activity of the antibacterial principles. The broad spectrum antibacterial activity of Aziridine, 1-(2-aminoethyl)-, was optimized by a one-variable-at-a-time system coupled with response surface methodology, which led to a 45% enhancement of the antibacterial activity. The maximum response (22.81 ± 0.16 mm of zone of inhibition against MRSA) was marked in 250 mL Erlenmeyer flask containing 90 mL potato dextrose broth supplemented with (g%/L) glucose, 9.7; urea concentration, 0.74; with medium pH 6.48; after 8.76 days of incubation at 26 °C. APS1 strongly inhibited biofilm formation in the tested pathogenic microorganisms and acts as a larvicidal agent against the Dengue-vector Aedes aegypti. This is probably the first report of Aziridine, 1-(2-aminoethyl)-, from any endophytic source. Cochliobolus sp. APS1 possesses industrial importance for the production of bioactive alkaloids.

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Zheng, Danni, Weida Fu, Lingli Jin, Xiaofang Jiang, Wenjie Jiang, Yaoyao Guan, and Rutian Hao. "The Overexpression and Clinical Significance of AP1S1 in Breast Cancer." Cancer Management and Research Volume 14 (April 2022): 1475–92. http://dx.doi.org/10.2147/cmar.s346519.

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Zhang, J., X. Y. Cheng, and G. Y. Sheng. "AP4M1 is abnormally expressed in oxygen–glucose deprived hippocampal neurons." Neuroscience Letters 563 (March 2014): 85–89. http://dx.doi.org/10.1016/j.neulet.2014.01.034.

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Howell, Sacha, Alice Greenhalgh, Robert Pedley, Suad Alghamdi, Amanda Caruso, Mujtaba Ansari, Tiago Moreira, et al. "Abstract P1-10-01: Results from the breast cancer - anti progestin prevention study 1 (BC-APPS1) trial - a novel approach in breast cancer prevention." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–10–01—P1–10–01. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-10-01.

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Abstract Background The luminal progenitor (LP) population in the normal breast is under the control of paracrine progesterone signalling and likely represents the cell of origin of estrogen receptor negative (ER-) BC. Exogenous progestins, as contraception or menopausal hormone replacement therapy (HRT), increase the risk of ER- and ER+ BC. We sought to examine the effect antagonism of progesterone signalling on the tissue composition and cellular hierarchy of normal human breast and thus the potential for progesterone receptor antagonism in breast cancer prevention. Methods BC-APPS1 is a single arm phase 2 pilot study in which premenopausal women at increased familial BC risk underwent vacuum assisted biopsy (VAB) in the luteal phase of the menstrual cycle prior to commencing a 12 week course of the selective progesterone receptor modulator (SPRM) ulipristal acetate (UA; 5mg daily). VAB was repeated in the final week of therapy. The primary endpoint of BC-APPS1 was change in epithelial Ki67 assessed by immunohistochemistry. Secondary endpoints included toxicity and additional tissue endpoints including immunofluorescence (IF) staining of LP markers, 2D mixed luminal/basal and 3D (mammosphere) colony formation assays, LP fraction by FACS (CD49f+/EPCAM+ cells), single cell and bulk RNAseq, epithelium/stromal laser capture microdissection-based proteomics and tissue stiffness analyses. Baseline samples were compared to a historic cohort of normal risk (n=25) and high risk (n=41) samples for IF analyses. Results Between 03/2016 and 03/2019 26 women were recruited to BC-APPS1 and 24 underwent paired biopsies. The trial met its primary endpoint with a significant reduction in median Ki67 between baseline (4.89%; IQR 4.36-10.42) and 12 weeks (2.41%; IQR 1.57-3.24; p<0.0001). Study procedures were well tolerated with minimal drug toxicity (all G1/2). 2 women discontinued UA due to anxiety: 1 drug induced and 1 induced following development of a small haematoma following VAB1. FACS analysis (n=17) demonstrated significant reduction in the LP proportion with UA treatment (median baseline 44.7% IQR 28.1-55.2 and 12 weeks 25.4% IQR 17.2-37.8; p<0.01). Breast tissue from high-risk women had increased expression of PR+ (10.8% vs 4.5%; p<0.01) and dual Sox9+Ki67+ cells (4.8% vs 0.8%, p<0.01). The Sox9+Ki67+ population reduced significantly with UA therapy in BC-APPS1 (4.4% vs 1.3%, p<0.05). In functional analyses both mammosphere and mixed luminal/basal colony formation reduced with UA treatment and single cell RNAseq (n=8 pairs) and epithelium/stromal laser capture microdissection-based proteomics (n=5 pairs) identified stromal components and remodelling as key pathways perturbed by UA treatment. Tissue stiffness, assessed by atomic force microscopy and previously shown to be positively associated with %mammographic density, was significantly reduced with UA treatment. Conclusions: High risk women have increased surrogate markers of BC risk including proliferating luminal progenitor cells which can be reduced by short term SPRM treatment with UA. Treatment is generally well tolerated and SPRM therapy is an attractive candidate for BC prevention. Longer term studies are warranted and stromal remodelling and breast tissue stiffness data suggest that mammographic density should be investigated as a potential surrogate biomarker of activity. Citation Format: Sacha Howell, Alice Greenhalgh, Robert Pedley, Suad Alghamdi, Amanda Caruso, Mujtaba Ansari, Tiago Moreira, Sue Astlet, Anthony Maxwell, Yit Lim, Hayley Brookes, Faiza Idries, Anthony Howell, D Gareth Evans, Michael Sherratt, Andrew Gilmore, Elaine Harkness, Walid Khaled, Alecia-Jane Twigger, Matt Roberts, Robert Clarke, Bruno Simoes. Results from the breast cancer - anti progestin prevention study 1 (BC-APPS1) trial - a novel approach in breast cancer prevention [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-10-01.

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DeVoss, Jason J., and Mark S. Anderson. "Lessons on immune tolerance from the monogenic disease APS1." Current Opinion in Genetics & Development 17, no. 3 (June 2007): 193–200. http://dx.doi.org/10.1016/j.gde.2007.04.001.

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Zhang, Xiaojing, Jingjing Wang, Kun Zhu, Yanyan Jin, Haidong Fu, and Jianhua Mao. "Activated phosphoinositide 3-kinase delta syndrome misdiagnosed as anti-neutrophil cytoplasmic antibody-associated vasculitis: a case report." Journal of International Medical Research 49, no. 5 (May 2021): 030006052110132. http://dx.doi.org/10.1177/03000605211013222.

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Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined inborn error of immunity mainly caused by PIK3CD mutations. We herein describe a 4-year-old Chinese boy who was admitted for recurrent pneumonia and persistent hematuria and exhibited multisystem involvement and anti-neutrophil cytoplasmic antibody (ANCA) positivity. He was initially diagnosed with ANCA-associated vasculitis. However, genetic testing revealed a c.1574A>G PIK3CD mutation, resulting in a diagnosis of APDS1.

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., Usmanullah, Ajmal Khan Bazai, Abdul Wadood Kakar, Muhammad Hanif, Shazia Ramzan, and Jamshed Khan. "Prevalence of Epilepsy with Autosomal Recessive Intellectual Disability in Consanguineous Families." Pakistan Journal of Medical and Health Sciences 16, no. 4 (April 29, 2022): 1195–97. http://dx.doi.org/10.53350/pjmhs221641195.

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Background: Intellectual disability (I.D) is the limitation of cognitive impairment and decreased ability of learning of a person. It is a type of neurological genetic disease, which results in incomplete or retarded/ arrested development of the brain. I.D is one of the most common health problem worldwide. These patients have decreased intellectual functions and at least limitation in their two adoptive skills such as writing or reading abilities, communication ability and self-care etc. While epilepsy is a neurodevelopment disease presented as abrupt & episodic recurrence of sensory disturbance, loss of consciousness or convulsions, related with the abnormality of electrical activities in the brain. Epilepsy is an illness of CNS that result in abnormal brain activity, causing periods of unusual behavior or seizures, loss of awareness, and sometimes sensations. Methods: This study was done from April 2014 to February 2016. The inclusion criteria for these patients were consanguineous families with two or more than two effected persons. All the I.D patients and their families were interviewed one by one. Blood samples were collected under hygienic method. Each patient were examined thoroughly and noted the points with the help of different proformas. Collected blood collection were stored in laboratory. After DNA extraction ,PCR was done. After extraction exome sequencing process used to find the pathogenic /effected variants. CATCH used for the analyzed of data. Sanger Sequencing was applied to note the segregation. Results: In ID-family1 the variant of AP4B1 was segregated with the disease phenotype. Mutation in AP4B1 is known to cause intellectual disability. In ID-family2 the variants of WDR62, EML2 and KCNK6 were co-segregated with diseased phenotype. But only changes in WDR62 which is known as a cause of intellectual disability. These patients also have symptoms of epilepsy. In ID-family3 exome sequencing data reveal no putative variants. Conclusion: This study was done in three consanguineous families to determine the responsible mutant genes for the disorder of intellectual disability. Their Exome sequencing showed putative mutations in AP4B1 and WDR62 in two out of three families. In third family we could not locate any putative mutation. Keywords: Epilepsy, Intellectual disability, Autosomal recessive disorders, Autosomal recessive nonsyndromic intellectual disability, Seizures, Neurological, Behavioral Abnormality, Central Nervous System, Electroencephalogram.

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Saadi, Abdelkrim, Chahinez Meftah, Laurence Colleaux, Amel Daidi, Hakim Gourari, Saadia Lougani, and Meriem Abada-Bendib. "Paraparésie spastique héréditaire due à une mutation homozygote du gène AP4M1." Revue Neurologique 173 (March 2017): S155. http://dx.doi.org/10.1016/j.neurol.2017.01.287.

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Chen, Xiuyin, Yar-Khing Yauk, Niels J. Nieuwenhuizen, Adam J. Matich, Mindy Y. Wang, Ramon Lopez Perez, Ross G. Atkinson, and Lesley L. Beuning. "Characterisation of an (S)-linalool synthase from kiwifruit (Actinidia arguta) that catalyses the first committed step in the production of floral lilac compounds." Functional Plant Biology 37, no. 3 (2010): 232. http://dx.doi.org/10.1071/fp09179.

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Kiwifruit (Actinidia spp. Lindl.) flowers and fruit contain many compounds of interest to the flavour and fragrance industries. In particular, Actinidia arguta (Sieb. et Zucc.) Planch. ex Miq. flowers produce β-linalool and important derivatives thereof, including linalool oxides, lilac aldehydes, alcohols and alcohol epoxides. Dynamic headspace sampling of whole A. arguta flowers showed that the peak emission rate of linalool, lilac alcohols and lilac aldehydes occurred around 0800 hours. After solvent extraction, linalool levels remained constant throughout the day and night, but lilac alcohol levels peaked at noon. In whole flowers, linalool was found predominantly in pistils and petals, and the lilac compounds were found mainly in petals. Two highly homologous (96.6% nucleotide identity) terpene synthase cDNA sequences, AaLS1 and ApLS1, were isolated from A. arguta and Actinidia polygama (Sieb. et Zucc.) Maxim flower EST libraries respectively. Real-time PCR analysis revealed that AaLS1 was expressed constitutively throughout the day and night, and primarily in petal tissue. Functional analysis in Escherichia coli showed that AaLS1 and ApLS1 each encoded a linalool synthase which was confirmed by transient expression in planta. Enantioselective gas chromatography revealed that both terpene synthases produced only (S)-(+)-linalool. AaLS1, therefore, is likely to be the key enzyme producing the (S)-linalool precursor of the lilac alcohols and aldehydes in A. arguta flowers.

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43

Sköldberg, Filip, Fredrik Rorsman, Jaakko Perheentupa, Mona Landin-Olsson, Eystein S. Husebye, Jan Gustafsson, and Olle Kämpe. "Analysis of Antibody Reactivity against Cysteine Sulfinic Acid Decarboxylase, A Pyridoxal Phosphate-Dependent Enzyme, in Endocrine Autoimmune Disease." Journal of Clinical Endocrinology & Metabolism 89, no. 4 (April 1, 2004): 1636–40. http://dx.doi.org/10.1210/jc.2003-031161.

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Abstract The structurally related group II pyridoxal phosphate (PLP)-dependent amino acid decarboxylases glutamic acid decarboxylase (GAD), aromatic l-amino acid decarboxylase (AADC), and histidine decarboxylase (HDC) are known autoantigens in endocrine disorders. We report, for the first time, the prevalence of serum autoantibody reactivity against cysteine sulfinic acid decarboxylase (CSAD), an enzyme that shares 50% amino acid identity with the 65- and 67-kDa isoforms of GAD (GAD-65 and GAD-67), in endocrine autoimmune disease. Three of 83 patients (3.6%) with autoimmune polyendocrine syndrome type 1 (APS1) were anti-CSAD positive in a radioimmunoprecipitation assay. Anti-CSAD antibodies cross-reacted with GAD-65, and the anti-CSAD-positive sera were also reactive with AADC and HDC. The low frequency of anti-CSAD reactivity is in striking contrast to the prevalence of antibodies against GAD-65, AADC, and HDC in APS1 patients, suggesting that different mechanisms control the immunological tolerance toward CSAD and the other group II decarboxylases. Moreover, CSAD may be a useful mold for the construction of recombinant chimerical antigens in attempts to map conformational epitopes on other group II PLP-dependent amino acid decarboxylases.

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Khan, Jamshed, Muhammad Hanif, Nayyer Uz Zaman, Dost Muhammad Khan, Muhammad Waqar, and Usmanullah . "Association of Spastic Paraplegia and Short Stature in Patients of Autosomal Recessive Intellectual Disability." Pakistan Journal of Medical and Health Sciences 16, no. 10 (October 30, 2022): 851–54. http://dx.doi.org/10.53350/pjmhs221610851.

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Background: Intellectual Disability “ID” is a genetic disorder, which lead to arrested or incomplete development of the brain. It is the limitation of cognitive skills impairment and decline ability of a person in learning process. ID is the most common health problem in worldwide. These patients have decline intellectual functions and at least limitation in their two or more adoptive skills such as reading, writing abilities, social interactions, Behavioral habits, self-care, communication ability etc. The time period for the diagnosis of ID is the onset of disease before the eighteen years of age. Spastic Paraplegia and short stature is a general terminology using for a group of an uncommon inherited diseases that cause stiffness and weakness in the lower limbs muscles. Gradually its symptoms get worse with the passing of time. It's also called as familial spastic paraparesis or Strümpell-Lorrain syndrome. SP is classified clinically as “complicated" (syndromic) or "uncomplicated" (nonsyndromic) Spastic Paraplegia. Methods: This study was started in March 2014 to Aug 2015. The criteria for the selection of families were consanguineous families with two or more than two ID patients. The patients were examined, interviewed one by one in friendly atmosphere. Then the blood samples were taken by aseptic method. Blood samples were processed in laboratory. DNA extraction and PCR was done. After that Exome sequencing was used to find the pathogenic variants. The data was analyzed by CATCH. Sanger Sequencing was applied to see the segregation. Results: In ID-family1 the variant of AP4B1 was segregated with the disease phenotype. These ID patients have short stature and Spastic Paraplegia. Mutation in AP4B1 is known to cause intellectual disability. In ID-family2 the variants of WDR62, EML2 and KCNK6 were co-segregated with disease phenotype. But only mutations in WDR62 are known to cause intellectual disability. ID family2 also identified as short stature. In ID-family3 Exome sequencing data reveal no putative variants. Conclusion: The present study was conducted in three consanguineous families for the determination of the responsible genes for intellectual disability. Exome sequencing revealed putative mutations in AP4B1 and WDR62 in two out of three families. In third family we could not locate any putative mutation. Keywords: Intellectual disability ID, Autosomal recessive disorders, Autosomal recessive nonsyndromic ID, Behavioral Abnormality, Segregation, Exome sequencing, Spastic Paraplegia, Short stature.

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45

Bauer, Peter, Esther Leshinsky-Silver, Lubov Blumkin, Nina Schlipf, Christopher Schröder, Julia Schicks, Dorit Lev, Olaf Riess, Tally Lerman-Sagie, and Ludger Schöls. "Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47)." neurogenetics 13, no. 1 (January 31, 2012): 73–76. http://dx.doi.org/10.1007/s10048-012-0314-0.

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46

Haq, Tahniyah, Anisur Rahman, and Shapur Ikhtaire. "Autoimmune polyendocrine syndrome type 1 a case report from Bangladesh." IMC Journal of Medical Science 10, no. 1 (January 12, 2017): 33–35. http://dx.doi.org/10.3329/imcjms.v10i1.31105.

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We describe a case of a 26 years old man who presented with adrenocortical insufficiency followed by hypoparathyroidism and subsequently mucocutaneous candidiasis. He also had nail dystrophy, cataract and alopecia, but no other endocrinopathies. He was diagnosed as a case of autoimmune polyendocrine syndrome type 1(APS 1). APS1 is a rare endocrine disorder and only a few cases have been reported from Bangladesh.

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47

Six, Anne, Khedidja Mosbahi, Madhuri Barge, Colin Kleanthous, Thomas Evans, and Daniel Walker. "Pyocin efficacy in a murine model of Pseudomonas aeruginosa sepsis." Journal of Antimicrobial Chemotherapy 76, no. 9 (June 18, 2021): 2317–24. http://dx.doi.org/10.1093/jac/dkab199.

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Abstract Background Bloodstream infections with antibiotic-resistant Pseudomonas aeruginosa are common and increasingly difficult to treat. Pyocins are naturally occurring protein antibiotics produced by P. aeruginosa that have potential for human use. Objectives To determine if pyocin treatment is effective in a murine model of sepsis with P. aeruginosa. Methods Recombinant pyocins S5 and AP41 were purified and tested for efficacy in a Galleria mellonella infection model and a murine model of P. aeruginosa sepsis. Results Both pyocins produced no adverse effects when injected alone into mice and showed good in vitro antipseudomonal activity. In an invertebrate model of sepsis using G. mellonella, both pyocins significantly prolonged survival from 1/10 (10%) survival in controls to 80%–100% survival among groups of 10 pyocin-treated larvae. Following injection into mice, both showed extensive distribution into different organs. When administered 5 h after infection, pyocin S5 significantly increased survival from 33% (2/6) to 83% (5/6) in a murine model of sepsis (difference significant by log-rank test, P < 0.05). Conclusions Pyocins S5 and AP41 show in vivo biological activity and can improve survival in two models of P. aeruginosa infection. They hold promise as novel antimicrobial agents for treatment of MDR infections with this microbe.

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48

Liston, Adrian, Daniel H. D. Gray, Sylvie Lesage, Anne L. Fletcher, Judith Wilson, Kylie E. Webster, Hamish S. Scott, Richard L. Boyd, Leena Peltonen, and Christopher C. Goodnow. "Gene Dosage–limiting Role of Aire in Thymic Expression, Clonal Deletion, and Organ-specific Autoimmunity." Journal of Experimental Medicine 200, no. 8 (October 18, 2004): 1015–26. http://dx.doi.org/10.1084/jem.20040581.

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Inactivation of the autoimmune regulator (Aire) gene causes a rare recessive disorder, autoimmune polyendocrine syndrome 1 (APS1), but it is not known if Aire-dependent tolerance mechanisms are susceptible to the quantitative genetic changes thought to underlie more common autoimmune diseases. In mice with a targeted mutation, complete loss of Aire abolished expression of an insulin promoter transgene in thymic epithelium, but had no effect in pancreatic islets or the testes. Loss of one copy of Aire diminished thymic expression of the endogenous insulin gene and the transgene, resulting in a 300% increase in islet-reactive CD4 T cells escaping thymic deletion in T cell receptor transgenic mice, and dramatically increased progression to diabetes. Thymic deletion induced by antigen under control of the thyroglobulin promoter was abolished in Aire homozygotes and less efficient in heterozygotes, providing an explanation for thyroid autoimmunity in APS1. In contrast, Aire deficiency had no effect on thymic deletion to antigen controlled by a systemic H-2K promoter. The sensitivity of Aire-dependent thymic deletion to small reductions in function makes this pathway a prime candidate for more subtle autoimmune quantitative trait loci, and suggests that methods to increase Aire activity would be a potent strategy to lower the incidence of organ-specific autoimmunity.

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49

Wu, Yiwen, Yi Huang, Chenhui Zhou, Haifeng Wang, Zhepei Wang, Jiawei Wu, Sheng Nie, Xinpeng Deng, Jie Sun, and Xiang Gao. "A Novel Necroptosis-Related Prognostic Signature of Glioblastoma Based on Transcriptomics Analysis and Single Cell Sequencing Analysis." Brain Sciences 12, no. 8 (July 26, 2022): 988. http://dx.doi.org/10.3390/brainsci12080988.

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Background: Glioblastoma (GBM) is the most common and deadly brain tumor. The clinical significance of necroptosis (NCPS) genes in GBM is unclear. The goal of this study is to reveal the potential prognostic NCPS genes associated with GBM, elucidate their functions, and establish an effective prognostic model for GBM patients. Methods: Firstly, the NCPS genes in GBM were identified by single-cell analysis of the GSE182109 dataset in the GEO database and weighted co-expression network analysis (WGCNA) of The Cancer Genome Atlas (TCGA) data. Three machine learning algorithms (Lasso, SVM-RFE, Boruta) combined with COX regression were used to build prognostic models. The subsequent analysis included survival, immune microenvironments, and mutations. Finally, the clinical significance of NCPS in GBM was explored by constructing nomograms. Results: We constructed a GBM prognostic model composed of NCPS-related genes, including CTSD, AP1S1, YWHAG, and IER3, which were validated to have good performance. According to the above prognostic model, GBM patients in the TCGA and CGGA groups could be divided into two groups according to NCPS, with significant differences in survival analysis between the two groups and a markedly worse prognostic status in the high NCPS group (p < 0.001). In addition, the high NCPS group had higher levels of immune checkpoint-related gene expression, suggesting that they may be more likely to benefit from immunotherapy. Conclusions: Four genes (CTSD, AP1S1, YWHAG, and IER3) were screened through three machine learning algorithms to construct a prognostic model for GBM. These key and novel diagnostic markers may become new targets for diagnosing and treating patients with GBM.

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Mayr, Bernhard, Dirk Schnabel, Helmuth-Günther Dörr, and Christof Schöfl. "GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts." European Journal of Endocrinology 174, no. 5 (May 2016): R189—R208. http://dx.doi.org/10.1530/eje-15-1028.

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The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of theCASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper- or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper- and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and aboutin vitroeffects of allosteric CASR modulators on mutated CASR. The therapeutic concepts for patients with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant hypocalcemia (ADH) are reviewed. FHH is usually benign, but symptomatic patients benefit from cinacalcet. In NSHPT patients pamidronate effectively lowers serum calcium, but most patients require parathyroidectomy. In some patients cinacalcet can obviate the need for surgery, particularly in heterozygous NHPT. Symptomatic ADH patients respond to vitamin D and calcium supplementation but this may increase calciuria and renal complications. PTH treatment can reduce relative hypercalciuria. None of the currently available therapies for ADH, however, prevent tissue calcifications and complications, which may become possible with calcilytics that correct the underlying pathophysiologic defect.

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