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Автор: Grafiati

Опубліковано: 7 липня 2024

Оновлено: 7 липня 2024

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1

Parvaz, Najmeh, and Zahra Jalali. "Molecular evolution of PCSK family: Analysis of natural selection rate and gene loss." PLOS ONE 16, no. 10 (October 28, 2021): e0259085. http://dx.doi.org/10.1371/journal.pone.0259085.

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Proprotein convertases subtilisin kexins are serine endoproteases, playing critical roles in the biological functions, including lipid, glucose, and bile acid metabolism, as well as cell proliferation, migration, and metastasis. Experimental studies have demonstrated the physiological functions of PCSKs and their association with diseases; however, studies on the evolutionary history and diversification of these proteins are missing. In the present research, a bioinformatics study was conducted on the molecular evolution of several PCSKs family members and gene loss events across placental mammalian. In order to detect evolutionary constraints and positive selection, the CodeML program of the PAML package was used. The results showed the positive selection to occur in PCSK1, PCSK3, PCSK5, and PCSK7. A decelerated rate of evolution was observed in PCSK7, PCSK3, and MBTPS1 in Carnivores compared to the rest of phylogeny, and an accelerated evolution of PCSK1, PCSK7, and MBTPS1 in Muridae family of rodents was found. Additionally, our results indicated pcsk9 gene loss in 12 species comprising Carnivores and bats (Chiroptera). Future studies are required to evaluate the functional relevance and selective evolutionary advantages associated with these modifications in PCSK proteins during evolution.

2

Gagnon, Jeffrey, Janice Mayne, Majambu Mbikay, John Woulfe, and Michel Chrétien. "Expression of PCSK1 (PC1/3), PCSK2 (PC2) and PCSK3 (furin) in mouse small intestine." Regulatory Peptides 152, no. 1-3 (January 2009): 54–60. http://dx.doi.org/10.1016/j.regpep.2008.07.006.

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3

Xu, Xu, Egor Volcotrub, and Svetlana B. Ten. "LBSUN131 Leptin Level, BMI And Genetics In Early Onset Obesity." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A5. http://dx.doi.org/10.1210/jendso/bvac150.009.

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Abstract Objective To evaluate leptin level and its association with BMI and genetic predisposition in cases of early onset obesity. Methods 76 children (15.3 ± 10 yrs, 47 females) with morbid obesity (BMI of 41.7 ± 5.7 kg/m2) and 2 fathers and 5 mothers of these patients with BMI 47.8 ± 8.7 kg/m2 underwent genetic testing at the Prevention Genetics after obtaining consent. Leptin, Lipid profile, Glucose, Insulin, ALT, AST were measured. Results From 83 cases heterozygous polymorphism was found in 65 and in 18 genetic analysis was negative. | Patients were divided into 3 groups according to the leptin level. | 13 patients had leptin level less than 12 ng/ml (7.9 ± 2.5) (Group 1) (5 patients - no mutation, 8 with different combination of the genes: 1 with (BBS14 (CEP290) and BBS10), 2 BBS5, 2 SH2B1, 1 PLXNA3, 1 with (PCSK1 and ALMS1), 1 with BBS 20 (IFT172). Leptin didn't correlate with BMI in this group. | 6 patients had leptin elevated more than 50 ng/ml (74.5 ± 17.7) (Group 2). (1 patient – no mutation, 1 with KSR2, 1 with MCR4, 1 with SEMA3G, 1 with a combination of MCR4 and 2 different POMC, 1 with PLXNA4 and BBS15 (WDPCP). Leptin didn't correlate with BMI in this group. | 64 patients had leptin level (24.6 ± 9.4 ng/ml) expected for their BMI (42.7 ± 8.5 kg/m2) (Group 3). Leptin level correlated with BMI (r=0.37, P=0. 002). In group 3, Genetic analysis was negative in 12 patients, 1 gene was in 19 cases (KSR2 in 3, PCSK1 in 4, POMC in 2, others in 1: BBS 17(KZTFL1), BBS9, BBS21 (C8orf37), BBC20(IFT172), MCR4, MRAP2, PLXNA4, POMC, INPP5E, UCP3. | 2 genes in 25 cases: (BBS1, NTRK2), (BBS4, RAI1), (BBS4, PLXNA3) (BBS7, NTRK2), (BBS2, BBS9), (BBS9, MCR4),(BBS9, ADCY3), (BBS9, ALMS1), (BBS10, ALMS1), (BBS10, BBS22 (IFT74)), (BBS13 (MKS1), PCKS1), (BBS14 (CEP290), PCSK1), (BBS15 (WDPCP), PCSK1), (BBS18, POMC), (BBS20(IFT172), PCSK1), (BBS 22 (IFT74), SH2B1), (ALMS1,PCSK1), (ALMS1, BDNF), (SH2B1, NCOA1), (SH2B1, PCSK1), (SEMA3G, NTRK2), (SEMA3D, UCP3), (SIM1, NROB2), (KSR2, NTRK2), (MRAP2, RPGRIP1L). | 3 genes in 5 cases (BBS16 (SDCCAG8), BBS14 (CEP290), KIDINS220), (KSR2, ALMS1, PCNT), (KSR2, SEMA3G, NTRK2), (ALMS1, PCSK1, NCOA1), (BBS9, ALMS1, TRIM32)4 genes in 2 cases (BBS9, BBS11(TRIM32), ALMS1, POMC) and (BBS19 (IFT27), BBS 20 (IFT27), SEMA3B, PLXNA3). | 5 genes in 1 case (BBS12, BBS20 (IFT172), ALMS1, RPGRIP1L, SEMA3G). There were no differences in age, BMI, Hb A1c, SBP, DBP, Glucose, Insulin HOMA. ALT, AST, TG, and HDL levels between groups. Conclusion There is a high frequency of genes involved in cilia regulation like BBS and ALMS1 genes. Identifying patients with low leptin level for the degree of obesity can individualize treatment to decrease appetite and increase energy expenditure Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

4

Clément, Karine, Martin Wabitsch, Erica Van den Akker, Jesús Argente, Ceclila Scimia, Madhura Srinivasan, Guojun Yuan, and Peter Kühnen. "ODP607 Long-term Efficacy of Setmelanotide in Patients With POMC or LEPR Deficiency Obesity." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A14—A15. http://dx.doi.org/10.1210/jendso/bvac150.030.

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Abstract The melanocortin-4 receptor (MC4R) pathway in the brain is responsible for energy regulation, affecting appetite and body weight. Impairments of this pathway can result in hyperphagia (insatiable hunger) and obesity. The MC4R can be impacted by the POMC, PCSK1, or LEPR genes. Variants in these genes that are inherited from both parents (biallelic) can result in MC4R pathway signaling deficiencies. Setmelanotide is a drug that activates the MC4R. In earlier Phase 3 studies, setmelanotide was shown to improve hunger and reduce weight in patients with POMC, PCSK1, and LEPR biallelic deficiency. The present study aims to examine the long-term efficacy of ∼3 years of setmelanotide treatment in patients with POMC, PCSK1, and LEPR biallelic deficiency in a long-term extension after a previous trial. Setmelanotide treatment continued to provide sizable reductions in body weight and body mass index while being generally well tolerated. These findings provide strong support of the safe and effective long-term use of setmelanotide to treat obesity in patients with POMC, PCSK1, and LEPR biallelic deficiency. Presentation: No date and time listed

5

Aerts, Laetitia, Nathalie A. Terry, Nina N. Sainath, Clarivet Torres, Martín G. Martín, Bruno Ramos-Molina, and John W. Creemers. "Novel Homozygous Inactivating Mutation in the PCSK1 Gene in an Infant with Congenital Malabsorptive Diarrhea." Genes 12, no. 5 (May 10, 2021): 710. http://dx.doi.org/10.3390/genes12050710.

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Proprotein convertase 1/3 (PC1/3), encoded by the PCSK1 gene, is expressed in neuronal and (entero)endocrine cell types, where it cleaves and hence activates a number of protein precursors that play a key role in energy homeostasis. Loss-of-function mutations in PCSK1 cause a recessive complex endocrinopathy characterized by malabsorptive diarrhea and early-onset obesity. Despite the fact that neonatal malabsorptive diarrhea is observed in all patients, it has remained understudied. The aim of this study was to investigate the enteroendocrine pathologies in a male patient with congenital PCSK1 deficiency carrying the novel homozygous c.1034A>C (p.E345A) mutation. This patient developed malabsorptive diarrhea and metabolic acidosis within the first week of life, but rapid weight gain was observed after total parenteral nutrition, and he displayed high proinsulin levels and low adrenocorticotropin. In vitro analysis showed that the p.E345A mutation in PC1/3 resulted in a (near) normal autocatalytic proPC1/3 processing and only partially impaired PC1/3 secretion, but the processing of a substrate in trans was completely blocked. Immunohistochemical staining did not reveal changes in the proGIP/GIP and proglucagon/GLP-1 ratio in colonic tissue. Hence, we report a novel PCSK1 deficient patient who, despite neonatal malabsorptive diarrhea, showed a normal morphology in the small intestine.

6

Velazquez-Roman, Jorge, Uriel A. Angulo-Zamudio, Nidia Leon-Sicairos, Hector Flores-Villaseñor, Miriam Benitez-Baez, Ana Espinoza-Salomón, Alejandra Karam-León, et al. "Association of PCSK1 and PPARG1 Allelic Variants with Obesity and Metabolic Syndrome in Mexican Adults." Genes 14, no. 9 (September 8, 2023): 1775. http://dx.doi.org/10.3390/genes14091775.

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Metabolic diseases, including obesity, diabetes, and metabolic syndrome, are among the most important public health challenges worldwide. Metabolic diseases are classified as multifactorial diseases in which genetic variants such as single-nucleotide polymorphisms (SNPs) may play an important role. The present study aimed to identify associations linking allelic variants of the PCSK1, TMEM18, GPX5, ZPR1, ZBTB16, and PPARG1 genes with anthropometric and biochemical traits and metabolic diseases (obesity or metabolic syndrome) in an adult population from northwestern Mexico. Methods: Blood samples were collected from 523 subjects, including 247 with normal weight, 276 with obesity, and 147 with metabolic syndrome. Anthropometric and biochemical characteristics were recorded, and single-nucleotide polymorphisms (SNPs) were genotyped by real-time PCR. Results: PCSK1 was significantly (p < 0.05) associated with BMI, weight, and waist-to-hip ratio; TMEM18 was significantly associated with systolic blood pressure and triglyceride levels; GPX5 was significantly associated with HDL cholesterol levels. In addition, PCSK1 was associated with obesity (p = 1.0 × 10−4) and metabolic syndrome (p = 3.0 × 10−3), whereas PPARG1 was associated with obesity (p = 0.044). Conclusions: The associations found in this study, mainly between allelic variants of PCSK1 and metabolic traits, obesity, and metabolic syndrome, may represent a risk for developing metabolic diseases in adult subjects from northwestern Mexico.

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Ayers, Kristin L., Benjamin S. Glicksberg, Alastair S. Garfield, Simonne Longerich, Joseph A. White, Pengwei Yang, Lei Du, et al. "Melanocortin 4 Receptor Pathway Dysfunction in Obesity: Patient Stratification Aimed at MC4R Agonist Treatment." Journal of Clinical Endocrinology & Metabolism 103, no. 7 (May 2, 2018): 2601–12. http://dx.doi.org/10.1210/jc.2018-00258.

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AbstractContextThe hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), orMC4R genes, have been shown to cause early-onset severe obesity.MethodsThrough a comprehensive epidemiological analysis of known and predicted LoF variants in thePOMC, PCSK1, andLEPR genes, we sought to estimate the number of US individuals with biallelic MC4R pathway LoF variants.ResultsWe predict ~650α-melanocyte-stimulating hormone (MSH)/POMC, 8500PCSK1, and 3600LEPR homozygous and compound heterozygous individuals in the United States, cumulatively enumerating >12,800 MC4R pathway–deficient obese patients. Few of these variants have been genetically diagnosed to date. These estimates increase when we include a small subset of less rare variants:β-MSH/POMC,PCSK1 N221D, and aPCSK1 LoF variant (T640A). To further define the MC4R pathway and its potential impact on obesity, we tested associations between body mass index (BMI) and LoF mutation burden in thePOMC, PCSK1, andLEPR genes in various populations. We show that the cumulative allele burden in individuals with two or more LoF alleles in one or more genes in the MC4R pathway are predisposed to a higher BMI than noncarriers or heterozygous LoF carriers with a defect in only one gene.ConclusionsOur analysis represents a genetically rationalized study of the hypothalamic MC4R pathway aimed at genetic patient stratification to determine which obese subpopulations should be studied to elucidate MC4R agonist (e.g., setmelanotide) treatment responsiveness.

8

Van Dijck, Evelien, Sigri Beckers, Sara Diels, Tammy Huybrechts, An Verrijken, Kim Van Hoorenbeeck, Stijn Verhulst, Guy Massa, Luc Van Gaal, and Wim Van Hul. "Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review." Genes 13, no. 10 (September 27, 2022): 1746. http://dx.doi.org/10.3390/genes13101746.

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Recently, it was reported that heterozygous PCSK1 variants, causing partial PC1/3 deficiency, result in a significant increased risk for obesity. This effect was almost exclusively generated by the rare p.Y181H (rs145592525, GRCh38.p13 NM_000439.5:c.541T>C) variant, which affects PC1/3 maturation but not enzymatic capacity. As most of the identified individuals with the heterozygous p.Y181H variant were of Belgian origin, we performed a follow-up study in a population of 481 children and adolescents with obesity, and 486 lean individuals. We identified three obese (0.62%) and four lean (0.82%) p.Y181H carriers (p = 0.506) through sanger sequencing and high resulting melting curve analysis, indicating no association with obesity. Haplotype analysis was performed in 13 p.Y181H carriers, 20 non-carriers (10 with obesity and 10 lean), and two p.Y181H families, and showed identical haplotypes for all heterozygous carriers (p < 0.001). Likewise, state-of-the-art literature concerning the role of rare heterozygous PCSK1 variants implies them to be rarely associated with monogenic obesity, as first-degree carrier relatives of patients with PC1/3 deficiency are mostly not reported to be obese. Furthermore, recent meta-analyses have only indicated a robust association for scarce disruptive heterozygous PCSK1 variants with obesity, while clinical significance is less or sometimes lacking for most nonsynonymous variants.

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Morash, Michael G., Angela B. MacDonald, Roger P. Croll, and Younes Anini. "Molecular cloning, ontogeny and tissue distribution of zebrafish (Danio rerio) prohormone convertases: pcsk1 and pcsk2." General and Comparative Endocrinology 162, no. 2 (June 2009): 179–87. http://dx.doi.org/10.1016/j.ygcen.2009.03.013.

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10

Sanders, SS. "PCSK1 variants: genetic risk factors for obesity." Clinical Genetics 75, no. 4 (April 2009): 318–19. http://dx.doi.org/10.1111/j.1399-0004.2009.01171_1.x.

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11

Farooqi, Sadaf, Jennifer Lynne Miller, Olga Ohayon, Guojun Yuan, Murray Stewart, Cecilia Scimia, and Jack Yanovski. "Effects of Setmelanotide in Patients With POMC, PCSK1, or LEPR Heterozygous Deficiency Obesity in a Phase 2 Study." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A669—A670. http://dx.doi.org/10.1210/jendso/bvab048.1367.

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Abstract Introduction: Setmelanotide is a melanocortin 4 receptor (MC4R) agonist being investigated for chronic weight management in patients with rare genetic diseases of obesity caused by impairment of the MC4R pathway. The objective of this analysis was to assess the efficacy and safety of setmelanotide in patients with partial insufficiency in the MC4R pathway due to heterozygous mutations in the POMC, PCSK1, or LEPR genes. Methods: This was an open-label, single-arm, Phase 2 study of setmelanotide in rare genetic diseases of obesity, including proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) heterozygous deficiency obesity (NCT03013543). Patients aged ≥6 years with POMC, PCSK1, or LEPR heterozygous deficiency obesity received once-daily setmelanotide, which was titrated for 4 weeks to establish the therapeutic dose of 3 mg daily. Treatment at the therapeutic dose continued for an additional 12 weeks. The primary endpoint was mean percent change from baseline in body weight at Month 3. Hunger scores and adverse events (AEs) were secondary endpoints. A responder was defined as having ≥5% weight loss from baseline at Month 3. Results: A total of 35 patients were included in this analysis, with mean (standard deviation) age of 39.5 (17.6) years and body mass index of 50.3 (9.4) kg/m2. Across all patients, the mean percent change in body weight from baseline to Month 3 was −3.7% (90% confidence interval [CI], −5.3% to −2.1%; n=35). A total of 34.3% of patients (12/35) achieved the responder threshold of ≥5% weight loss from baseline at Month 3. The mean percent change in body weight from baseline to Month 3 was −10.1% (90% CI, −12.4% to −7.9%; n=12) and −0.4% (90% CI, −1.2% to −0.5%; n=23) for responders and nonresponders, respectively. The mean percent change in most hunger score from baseline to Month 3 was −4.4% (90% CI, −5.7% to −3.2%; n=10) and −2.3% (90% CI, −3.2% to −1.5%; n=23) for responders and nonresponders, respectively. Among responders, 4 (33%) had variants that were considered pathogenic/likely pathogenic per American College of Medical Genetics criteria. All patients experienced at least 1 AE. Overall, the most common treatment-emergent AEs were skin hyperpigmentation (51.4%), nausea (48.6%), and injection site pruritis (37.8%). One patient had serious AEs of acute myocardial infarction and gastrointestinal hemorrhage that were considered unrelated to setmelanotide. No AEs led to death. Conclusions: Setmelanotide was associated with reduced body weight and hunger scores in patients with POMC, PCSK1, or LEPR heterozygous deficiency obesity. While the overall mean percent decrease in body weight may have been less than that previously reported in patients with homozygous or compound heterozygous variants, setmelanotide may be a viable treatment option for some patients with POMC, PCSK1, or LEPR heterozygous deficiency obesity.

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Clément, Karine, Erica L. T. van den Akker, Gregory Gordon, Guojun Yuan, and Peter Kühnen. "Timing of Onset of Adverse Events With Setmelanotide, an MC4R Agonist, in Patients With Severe Obesity Due to LEPR or POMC Deficiency." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A30—A31. http://dx.doi.org/10.1210/jendso/bvab048.058.

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Abstract Introduction: Setmelanotide is a melanocortin 4 receptor agonist indicated for chronic weight management in patients with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. This analysis aimed to assess the timing of the onset of adverse events (AEs) of special interest in patients with POMC/PCSK1 or LEPR deficiency obesity treated with setmelanotide. Methods: The timing of AE onset with setmelanotide was evaluated in a pooled set of patients with POMC/PCSK1 or LEPR deficiency who received setmelanotide in Phase 2 (RM-493-011 [NCT02507492]) or Phase 3 (RM-493-012 [NCT02896192] and RM-493-015 [NCT03287960]) clinical trials. Patients in the Phase 2 investigator-initiated trial (Charité Universitätsmedizin Berlin) received open-label setmelanotide for 12 to 13 weeks followed by an extension study for eligible patients. The Phase 3 trials included a 12-week open-label phase, an 8-week placebo-controlled phase, and a subsequent 32-week open-label phase, for a total treatment length of at least 1 year. AEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). AEs of special interest were defined as those related to treatment-emergent AEs (TEAEs) commonly occurring with setmelanotide (hyperpigmentation disorders, disturbances in sexual arousal, nausea, vomiting, injection site reactions [ISRs]). Results: As of November 10, 2020, 35 patients (15 POMC, 2 PCSK1, 18 LEPR) were enrolled and included across the 3 trials; 2 patients in the Phase 2 trial were ongoing treatment as of the cutoff. Daily setmelanotide dose ranged from 0.25 to 3.0 mg. All patients experienced ≥1 TEAE, the most common being skin hyperpigmentation (85.7%), injection site erythema (68.6%), nausea (57.1%), and headache (51.4%). For AEs of special interest, hyperpigmentation disorders occurred in 85.7% of patients (30/35), disturbances in sexual arousal in 17.1% (6/35), nausea in 57.1% (20/35), vomiting in 28.6% (10/35), and ISRs in 88.6% (31/35). The onset of most hyperpigmentation disorder (34/53 events; 64.2%) and disturbances in sexual arousal (6/11 events; 54.6%) AEs were during Month 1 after starting setmelanotide. Onset of nausea and vomiting were most frequent during Month 1 of treatment (nausea: 12/34 events [35.3%]; vomiting: 6/19 events [31.6%]). ISRs occurred throughout the trial, with 41.6% (91/219 events) having an onset within Month 1 of treatment. Eighteen serious AEs occurred, none were interpreted as related to the study drug. Conclusions: In patients with POMC/PCSK1 or LEPR deficiency obesity who received setmelanotide treatment, the onset of AEs of special interest in any month was generally highest during Month 1 of treatment, with fewer events occurring during subsequent months. Apart from hyperpigmentation, all AEs occurred intermittently.

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Wabitsch, Martin, Sadaf Farooqi, Jesús Argente, Erica van den Akker, Guojun Yuan, Olga Ohayon, and Cecilia Scimia. "RF24 | PSUN96 Setmelanotide in Patients With Heterozygous POMC, LEPR, SRC1, or SH2B1 Obesity: Design of EMANATE – A Placebo-Controlled Phase 3 Trial." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A37. http://dx.doi.org/10.1210/jendso/bvac150.076.

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Abstract Background The central hypothalamic melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Certain variants in genes upstream of MC4R, including those encoding the leptin receptor (LEPR), proopiomelanocortin (POMC), steroid receptor coactivator 1 (SRC1; also known as NCOA1), prohormone convertase (PC)1/3 (encoded by the gene PCSK1), and SH2B adaptor protein 1 (SH2B1) genes, lead to impaired MC4R pathway signaling and rare genetic diseases of obesity. While the deficiencies resulting from these genetic variants differ in some clinical features, they are all characterized by hyperphagia (pathologic insatiable hunger) and early-onset obesity during childhood. Setmelanotide, an MC4R agonist, reduced body weight and hyperphagia (assessed by hunger scores) after 3 months in patients with heterozygous POMC, including patients with the N221D variant in PCSK1; LEPR; SRC1; and SH2B1 (including a 220–kilobase pair distal deletion of chromosome 16p11.2) variants in an earlier Phase 2 trial. In the Phase 2 trial, 12 of 35 (34%) patients with heterozygous POMC, PCSK1, or LEPR variants; 9 of 30 patients (30%) with heterozygous SRC1 variants; and 13 of 35 (37%) patients with heterozygous SH2B1 variants achieved ≥5% weight loss after 3 months of setmelanotide treatment. Methods EMANATE is a randomized, double-blind, placebo-controlled Phase 3 trial (NCT05093634) comprising 5 similar independent sub-studies based on genetic variants. For eligibility, patients must be 6-65 years old, have history of hyperphagia and childhood obesity, current obesity defined as BMI ≥30 kg/m2 (in those ≥18 years old), and BMI ≥95th percentile (in those 6-17 years old). Patients must also have a heterozygous genetic variant in POMC or PCSK1; heterozygous genetic variant in LEPR; a homozygous, heterozygous, or compound heterozygous variant in SRC1 or SH2B1 (including a chromosomal deletion of 16p11.2 including SH2B1); or a heterozygous N221D variant in PCSK1. Patients with ≥2% weight loss in the prior 3 months, HbA1C >10%, clinically significant pulmonary, cardiac, or oncological disease, or history of significant liver or serious kidney disease are not eligible. Within each sub-study, patients will be randomized 1: 1 to receive daily subcutaneous injections of setmelanotide or placebo for 52 weeks. The primary outcome is the mean change in body weight in patients who receive setmelanotide compared with placebo. Safety will be assessed by frequency and severity of adverse events. Current Status: EMANATE is currently underway and began enrolling patients in early 2022. The planned enrollment is 560 patients. If successful, this placebo-controlled Phase 3 trial will support setmelanotide treatment for improvements in body weight–related measures and hunger in an expanded population of patients living with rare genetic diseases of obesity. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:12 p.m. - 1:17 p.m.

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Farooqi, Sadaf, Jennifer Miller, Olga Ohayan, Cecilia Scimia, Christopher Still, Marianne Yohn, Guojun Yuan, Jesús Argente, and Brieana Buckley. "OR10-1 Body Mass Index and Weight Reductions in Patients With Obesity Due to Heterozygous Variants in POMC, PCSK1, and LEPR After 1 Year of Setmelanotide." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A15. http://dx.doi.org/10.1210/jendso/bvac150.031.

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Abstract Background The melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Heterozygous variants of the genes for proopiomelanocortin (POMC), leptin receptor (LEPR), and proprotein convertase subtilisin/kexin type 1 (PCSK1) upstream of MC4R can result in impaired signaling in the MC4R pathway. This impaired signaling can lead to hyperphagia and early-onset, severe obesity. Setmelanotide (SET), an MC4R agonist, reduced weight and hunger after 3 months in patients with obesity due to these heterozygous variants in an earlier Phase 2 study. The current analysis is the first to assess continued efficacy of an additional year of SET treatment in patients with obesity due to heterozygous affectation of POMC, PCSK1, and LEPR. Methods Patients aged ≥6 years with obesity due to heterozygous variants in POMC, PCSK1, and LEPR were eligible for this long-term extension (LTE) trial (NCT03651765) after completing an index trial in which they received SET and demonstrated clinical benefit and acceptable safety as determined by the investigator. Patients received a minimum of 4 months of SET treatment in the index trial and began the LTE immediately following the completion of the index trial. Study visits occurred every 3 months and evaluated changes in body weight measures and assessed safety and tolerability. The current analysis reports outcomes after 1 year total of SET treatment across the index and LTE trials, relative to index trial baseline. Results As of October 29, 2021, 35 patients with obesity heterozygous for POMC, PCSK1, and LEPR had enrolled in the index trial, with 16, 17, and 17 patients continuing into the LTE trial and receiving at least 6, 9, and 12 months of treatment with SET, respectively. At index trial baseline, mean (standard deviation [SD]) body mass index (BMI) for all index trial patients was 50.26 (9.41) kg/m2, body weight in patients ≥18 years old was 142.97 (28.70) kg, and BMI Z score in patients <18 years old was 4.04 (0.65). Mean (SD) percent change in BMI was −6.93% (9.13%; n=16), −8.14% (10.13%; n=17), and −7.83% (9.69%; n=17) after 6, 9, and 12 months of treatment, respectively. Of 15 patients ≥18 years old, the mean (SD) percent change in body weight was −10.24% (7.90%; n=15) after 12 months. For the 1 patient <18 years old, mean change in BMI Z score was 0.64 after 12 months. No new safety concerns emerged during the LTE and 1 patient discontinued due to an adverse event, likely unrelated to treatment. Conclusions Treatment with SET had continued efficacy in patients with obesity due to heterozygous variants in POMC, PCSK1, and LEPR after 1 year of treatment. These data support the continued investigation of SET in these patients, which is underway in the Phase 3 EMANATE trial (NCT05093634). Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 a.m.

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Pickett, Lindsay A., Michael Yourshaw, Valeria Albornoz, Zijun Chen, R. Sergio Solorzano-Vargas, Stanley F. Nelson, Martín G. Martín, and Iris Lindberg. "Functional Consequences of a Novel Variant of PCSK1." PLoS ONE 8, no. 1 (January 28, 2013): e55065. http://dx.doi.org/10.1371/journal.pone.0055065.

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Herrmann, G., M. Wabitsch, and J. von Schnurbein. "Monogene Formen der Adipositas beim Menschen." Adipositas - Ursachen, Folgeerkrankungen, Therapie 12, no. 04 (December 2018): 162–67. http://dx.doi.org/10.1055/s-0038-1676672.

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ZusammenfassungEs gilt Patienten mit sehr seltenen Formen der monogenen Adipositas zu identifizieren um ihnen eine optimierte oder bestenfalls sogar kausale Therapie anbieten zu können. Hinweise für eine monogene Adipositasform sind insbesondere extreme Adipositas, frühkindlicher Beginn der Adipositas, sowie auffälliges Essverhalten mit Hyperphagie, ausgeprägtem nahrungssuchendem Verhalten und fehlendem Sättigungsgefühl. Mutationen in Genen, die den Leptin-Melanocortin-Signalweg betreffen, verursachen die wichtigsten Formen der monogenen Adipositas. Dabei sind Mutationen im Melanocortin-4-Rezeptor Gen (MC4R) am häufigsten. Zu einer ausgeprägten frühkindlichen Adipositas kommt es bei autosomal rezessiv vererbten Mutationen in den Genen für Leptin (LEP), Leptinrezeptor (LEPR), Proopiomelanocortin (POMC) und Prohormonkonvertase 1/3 (PCSK1). Eine kausale Therapie ist bei biologisch inaktivem Leptin oder Leptinmangel durch die Gabe von humanem rekombinantem Leptin verfügbar. Zudem gibt es mit dem MC4R -Agonisten (Setmelanotide) eine kausale Therapieoption für Patienten mit POMC-Mutation. Für Patienten mit Mutationen in MC4R, LEPR, PCSK1 finden aktuell klinische Studien hierzu statt, so dass in Zukunft eine kausale Therapie denkbar ist.

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Benzinou, Michael, John W. M. Creemers, Helene Choquet, Stephane Lobbens, Christian Dina, Emmanuelle Durand, Audrey Guerardel, et al. "Common nonsynonymous variants in PCSK1 confer risk of obesity." Nature Genetics 40, no. 8 (July 6, 2008): 943–45. http://dx.doi.org/10.1038/ng.177.

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Chrétien, Michel, and Majambu Mbikay. "60 YEARS OF POMC: From the prohormone theory to pro-opiomelanocortin and to proprotein convertases (PCSK1 to PCSK9)." Journal of Molecular Endocrinology 56, no. 4 (May 2016): T49—T62. http://dx.doi.org/10.1530/jme-15-0261.

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Pro-opiomelanocortin (POMC), is a polyprotein expressed in the pituitary and the brain where it is proteolytically processed into peptide hormones and neuropeptides with distinct biological activities. It is the prototype of multipotent prohormones. The prohormone theory was first suggested in 1967 when Chrétien and Li discovered γ-lipotropin and observed that (i) it was part of β-lipotropin (β-LPH), a larger polypeptide characterized 2 years earlier and (ii) its C-terminus was β-melanocyte-stimulating hormone (β-MSH). This discovery led them to propose that the lipotropins might be related biosynthetically to the biologically active β-MSH in a precursor to end product relationship. The theory was widely confirmed in subsequent years. As we celebrate the 50th anniversary of the sequencing of β-LPH, we reflect over the lessons learned from the sequencing of those proteins; we explain their extension to the larger POMC precursor; we examine how the theory of precursor endoproteolysis they inspired became relevant for vast fields in biology; and how it led, after a long and arduous search, to the novel proteolytic enzymes called proprotein convertases. This family of nine enzymes plays multifaceted functions in growth, development, metabolism, endocrine, and brain functions. Their genetics has provided many insights into health and disease. Their therapeutic targeting is foreseeable in the near future. Thus, what started five decades ago as a theory based on POMC fragments, has opened up novel and productive avenues of biological and medical research, including, for our own current interest, a highly intriguing hypocholesterolemic Gln152His PCSK9 mutation in French-Canadian families.

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Zheng, Xiaoya, Wei Ren, Suhua Zhang, Jingjing Liu, Sufang Li, Jinchao Li, Ping Yang, Jun He, Shaochu Su, and Ping Li. "Association of type 2 diabetes susceptibility genes (TCF7L2, SLC30A8, PCSK1 and PCSK2) and proinsulin conversion in a Chinese population." Molecular Biology Reports 39, no. 1 (March 25, 2011): 17–23. http://dx.doi.org/10.1007/s11033-011-0705-6.

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Stijnen, Pieter, Bruno Ramos-Molina, Stephen O'Rahilly, and John W. M. Creemers. "PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders." Endocrine Reviews 37, no. 4 (May 17, 2016): 347–71. http://dx.doi.org/10.1210/er.2015-1117.

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Ramos-Molina, Bruno, María Molina-Vega, José Fernández-García, and John Creemers. "Hyperphagia and Obesity in Prader–Willi Syndrome: PCSK1 Deficiency and Beyond?" Genes 9, no. 6 (June 7, 2018): 288. http://dx.doi.org/10.3390/genes9060288.

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Gu, Q., M. Yazdanpanah, M. van Hoek, A. Hofman, X. Gao, F. W. M. de Rooij, and E. J. G. Sijbrands. "Common variants in PCSK1 influence blood pressure and body mass index." Journal of Human Hypertension 29, no. 2 (July 17, 2014): 82–86. http://dx.doi.org/10.1038/jhh.2014.59.

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Frank, Graeme R., Joyce Fox, Ninfa Candela, Zorica Jovanovic, Elena Bochukova, Jeremiah Levine, Peter R. Papenhausen, Stephen O'Rahilly, and I. Sadaf Farooqi. "Severe obesity and diabetes insipidus in a patient with PCSK1 deficiency." Molecular Genetics and Metabolism 110, no. 1-2 (September 2013): 191–94. http://dx.doi.org/10.1016/j.ymgme.2013.04.005.

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Chang, Yi-Cheng, Yen-Feng Chiu, Kuang-Chung Shih, Ming-Wei Lin, Wayne Huey-Herng Sheu, Timothy Donlon, Jess David Curb, et al. "Common PCSK1 Haplotypes Are Associated With Obesity in the Chinese Population." Obesity 18, no. 7 (July 2010): 1404–9. http://dx.doi.org/10.1038/oby.2009.390.

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Maly Majeed, Anas Hussain. "In-Silico Analysis of Nonsynonymous Single Nucleotide Polymorphism in Human PCSK1 Gene." Bioscience Biotechnology Research Communications 14, no. 1 (March 25, 2021): 215–19. http://dx.doi.org/10.21786/bbrc/14.1/31.

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TAYLOR, AUSTIN, YI-CHUN CHEN, and BRUCE VERCHERE. "2105-P: Beta Cell PCSK1 Deficiency Increases Diabetes Susceptibility in Male Mice." Diabetes 69, Supplement 1 (June 2020): 2105—P. http://dx.doi.org/10.2337/db20-2105-p.

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Shan, Limin, Jiajie Sun, Chunlei Zhang, Xingtang Fang, Chuzhao Lei, Xianyong Lan, and Hong Chen. "The polymorphisms of bovine PCSK1 gene and their associations with growth traits." Genes & Genomics 33, no. 1 (February 2011): 57–63. http://dx.doi.org/10.1007/s13258-010-0049-y.

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Muhsin, Nor I. A., Liz Bentley, Ying Bai, Michelle Goldsworthy, and Roger D. Cox. "A novel mutation in the mouse Pcsk1 gene showing obesity and diabetes." Mammalian Genome 31, no. 1-2 (January 23, 2020): 17–29. http://dx.doi.org/10.1007/s00335-020-09826-4.

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Kaur, Harleen, Beverly S. Muhlhausler, Pamela Su-Lin Sim, Amanda J. Page, Hui Li, Maria Nunez-Salces, Georgia S. Clarke, et al. "Pregnancy, but not dietary octanoic acid supplementation, stimulates the ghrelin-pituitary growth hormone axis in mice." Journal of Endocrinology 245, no. 2 (May 2020): 327–42. http://dx.doi.org/10.1530/joe-20-0072.

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Circulating growth hormone (GH) concentrations increase during pregnancy in mice and remain pituitary-derived. Whether abundance or activation of the GH secretagogue ghrelin increase during pregnancy, or in response to dietary octanoic acid supplementation, is unclear. We therefore measured circulating GH profiles in late pregnant C57BL/6J mice and in aged-matched non-pregnant females fed with standard laboratory chow supplemented with 5% octanoic or palmitic (control) acid (n = 4–13/group). Serum total and acyl-ghrelin concentrations, stomach and placenta ghrelin mRNA and protein expression, Pcsk1 (encoding prohormone convertase 1/3) and Mboat4 (membrane bound O-acyl transferase 4) mRNA were determined at zeitgeber (ZT) 13 and ZT23. Total and basal GH secretion were higher in late pregnant than non-pregnant mice (P < 0.001), regardless of diet. At ZT13, serum concentrations of total ghrelin (P = 0.004), but not acyl-ghrelin, and the density of ghrelin-positive cells in the gastric antrum (P = 0.019) were higher, and gastric Mboat4 and Pcsk1 mRNA expression were lower in pregnant than non-pregnant mice at ZT23. In the placenta, ghrelin protein was localised mostly to labyrinthine trophoblast cells. Serum acyl-, but not total, ghrelin was lower at mid-pregnancy than in non-pregnant mice, but not different at early or late pregnancy. In conclusion, dietary supplementation with 5% octanoic acid did not increase activation of ghrelin in female mice. Our results further suggest that increases in maternal GH secretion throughout murine pregnancy are not due to circulating acyl-ghrelin acting at the pituitary. Nevertheless, time-dependent increased circulating total ghrelin could potentially increase ghrelin action in tissues that express the acylating enzyme and receptor.

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Blanco, Elias H., Bruno Ramos-Molina, and Iris Lindberg. "Revisiting PC1/3 Mutants: Dominant-Negative Effect of Endoplasmic Reticulum-Retained Mutants." Endocrinology 156, no. 10 (July 24, 2015): 3625–37. http://dx.doi.org/10.1210/en.2015-1068.

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Prohormone convertase 1/3 (PC1/3), encoded by the gene PCSK1, is critical for peptide hormone synthesis. An increasing number of studies have shown that inactivating mutations in PCSK1 are correlated with endocrine pathologies ranging from intestinal dysfunction to morbid obesity, whereas the common nonsynonymous polymorphisms rs6232 (N221D) and rs6234–rs6235 (Q665E-S690T) are highly associated with obesity risk. In this report, we revisited the biochemical and cellular properties of PC1/3 variants in the context of a wild-type PC1/3 background instead of the S357G hypermorph background used for all previous studies. In the wild-type background the PC1/3 N221D variant exhibited 30% lower enzymatic activity in a fluorogenic assay than wild-type PC1/3; this inhibition was greater than that detected in an equivalent experiment using the PC1/3 S357G background. A PC1/3 variant with the linked carboxyl-terminal polymorphisms Q665E-S690T did not show this difference. We also analyzed the biochemical properties of 2 PC1/3 mutants, G209R and G593R, which are retained in the endoplasmic reticulum (ER), and studied their effects on wild-type PC1/3. The expression of ER-retained mutants induced ER stress markers and also resulted in dominant-negative blockade of wild-type PC1/3 prodomain cleavage and decreased expression of wild-type PC1/3, suggesting facilitation of the entry of wild-type protein to a degradative proteasomal pathway. Dominant-negative effects of PC1/3 mutations on the expression and maturation of wild-type protein, with consequential effects on PC1/3 availability, add a new element which must be considered in population and clinical studies of this gene.

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Du, Qingyang, Rui Shao, Wentao Wang, Hui Zhang, Xinmeng Liao, Zhihao Wang, Zhan Yin, et al. "Vitamin D3 Regulates Energy Homeostasis under Short-Term Fasting Condition in Zebrafish (Danio Rerio)." Nutrients 16, no. 9 (April 25, 2024): 1271. http://dx.doi.org/10.3390/nu16091271.

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Vitamin D3 (VD3) is a steroid hormone that plays pivotal roles in pathophysiology, and 1,25(OH)2D3 is the most active form of VD3. In the current study, the crucial role of VD3 in maintaining energy homeostasis under short-term fasting conditions was investigated. Our results confirmed that glucose-depriving pathways were inhibited while glucose-producing pathways were strengthened in zebrafish after fasting for 24 or 48 h. Moreover, VD3 anabolism in zebrafish was significantly suppressed in a time-dependent manner under short-fasting conditions. After fasting for 24 or 48 h, zebrafish fed with VD3 displayed a higher gluconeogenesis level and lower glycolysis level in the liver, and the serum glucose was maintained at higher levels, compared to those fed without VD3. Additionally, VD3 augmented the expression of fatty acids (FAs) transporter cd36 and lipogenesis in the liver, while enhancing lipolysis in the dorsal muscle. Similar results were obtained in cyp2r1−/− zebrafish, in which VD3 metabolism is obstructed. Importantly, it was observed that VD3 induced the production of gut GLP-1, which is considered to possess a potent gluconeogenic function in zebrafish. Meanwhile, the gene expression of proprotein convertase subtilisin/kexin type 1 (pcsk1), a GLP-1 processing enzyme, was also induced in the intestine of short-term fasted zebrafish. Notably, gut microbiota and its metabolite acetate were involved in VD3-regulated pcsk1 expression and GLP-1 production under short-term fasting conditions. In summary, our study demonstrated that VD3 regulated GLP-1 production in zebrafish by influencing gut microbiota and its metabolite, contributing to energy homeostasis and ameliorating hypoglycemia under short-term fasting conditions.

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Duclaux-Loras, Rémi, Patrice Bourgeois, Pierre-Marie Lavrut, Fabienne Charbit-Henrion, Pauline Bonniaud-Blot, Raphael Maudinas, Marie Bournez, et al. "A novel mutation of PCSK1 responsible for PC1/3 deficiency in two siblings." Clinics and Research in Hepatology and Gastroenterology 45, no. 6 (November 2021): 101640. http://dx.doi.org/10.1016/j.clinre.2021.101640.

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Pyun, Jung-A., Sunshin Kim, Dong Hyun Cha, and KyuBum Kwack. "Epistasis between polymorphisms in PCSK1 and DBH is associated with premature ovarian failure." Menopause 21, no. 11 (November 2014): 1249–53. http://dx.doi.org/10.1097/gme.0000000000000226.

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Zhang, Hui, Xiaoxiang Hu, Zhipeng Wang, Yuandan Zhang, Shouzhi Wang, Ning Wang, Li Ma, et al. "Selection Signature Analysis Implicates the PC1/PCSK1 Region for Chicken Abdominal Fat Content." PLoS ONE 7, no. 7 (July 11, 2012): e40736. http://dx.doi.org/10.1371/journal.pone.0040736.

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Kummerfeld, Delf-Magnus, Boris V. Skryabin, Juergen Brosius, Sergey Y. Vakhrushev, and Timofey S. Rozhdestvensky. "Reference Genes across Nine Brain Areas of Wild Type and Prader-Willi Syndrome Mice: Assessing Differences in Igfbp7, Pcsk1, Nhlh2 and Nlgn3 Expression." International Journal of Molecular Sciences 23, no. 15 (August 5, 2022): 8729. http://dx.doi.org/10.3390/ijms23158729.

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Prader–Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by the deletion or inactivation of paternally expressed imprinted genes at the chromosomal region 15q11–q13. The PWS-critical region (PWScr) harbors tandemly repeated non-protein coding IPW-A exons hosting the intronic SNORD116 snoRNA gene array that is predominantly expressed in brain. Paternal deletion of PWScr is associated with key PWS symptoms in humans and growth retardation in mice (PWScr model). Dysregulation of the hypothalamic–pituitary axis (HPA) is thought to be causally involved in the PWS phenotype. Here we performed a comprehensive reverse transcription quantitative PCR (RT-qPCR) analysis across nine different brain regions of wild-type (WT) and PWScr mice to identify stably expressed reference genes. Four methods (Delta Ct, BestKeeper, Normfinder and Genorm) were applied to rank 11 selected reference gene candidates according to their expression stability. The resulting panel consists of the top three most stably expressed genes suitable for gene-expression profiling and comparative transcriptome analysis of WT and/or PWScr mouse brain regions. Using these reference genes, we revealed significant differences in the expression patterns of Igfbp7, Nlgn3 and three HPA associated genes: Pcsk1, Pcsk2 and Nhlh2 across investigated brain regions of wild-type and PWScr mice. Our results raise a reasonable doubt on the involvement of the Snord116 in posttranscriptional regulation of Nlgn3 and Nhlh2 genes. We provide a valuable tool for expression analysis of specific genes across different areas of the mouse brain and for comparative investigation of PWScr mouse models to discover and verify different regulatory pathways affecting this complex disorder.

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García-Martínez, A., D. A. Cano, A. Flores-Martínez, J. Gil, M. Puig-Domingo, S. M. Webb, A. Soto-Moreno, and A. Picó. "Why don’t corticotroph tumors always produce Cushing’s disease?" European Journal of Endocrinology 181, no. 3 (September 2019): 351–61. http://dx.doi.org/10.1530/eje-19-0338.

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Objective Silent corticotroph tumors are a pituitary neuroendocrine tumor subtype of corticotroph lineage that do not clinically express Cushing’s disease. The silencing of this type of tumor is not fully understood. The aim of the present study was to delve into the lack of secretory activity, studying the post-transcriptional and post-translational regulation of POMC/ACTH in a series of molecularly identified functioning and silent corticotroph tumors. Design We analyzed 24 silent corticotroph, 23 functioning corticotroph and 25 silent gonadotroph tumors. Methods We used Sanger sequencing, quantitative real-time PCR and Western blot to analyze genetic alterations in POMC, gene expression of TBX19, NEUROD1, POMC, PCSK1, PCSK2, CPE and PAM and protein expression of POMC, PC1/3, PC2, CPE and PAM. Results We found different polymorphisms in the POMC gene of corticotroph tumors, some of them related to deficiency of proopiomelanocortin. Silent corticotroph tumors showed lower PC1/3 gene and protein expression than functioning ones, especially compared to micro-functioning corticotroph tumors (all P < 0.05). Moreover, we found a positive correlation between PC2 and CPE gene and protein expression (rho ≥ 0.670, P < 0.009) in silent corticotroph tumors compared with functioning ones. Conclusions By studying the post-transcriptional and post-translational processing of POMC and ACTH, respectively, in a large series of silent and functioning corticotroph tumors, we found that the lack of secretory activity of these tumors is related to an impaired processing of POMC and a high degradation of ACTH, with the macro-functioning corticotroph tumor behaving as an intermediate state between micro-functioning and silent corticotroph tumors.

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Panigrahi, Sunil K., Kana Meece, and Sharon L. Wardlaw. "Effects of Naltrexone on Energy Balance and Hypothalamic Melanocortin Peptides in Male Mice Fed a High-Fat Diet." Journal of the Endocrine Society 3, no. 3 (January 28, 2019): 590–601. http://dx.doi.org/10.1210/js.2018-00379.

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Abstract The hypothalamic melanocortin system composed of proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons plays a key role in maintaining energy homeostasis. The POMC-derived peptides, α-MSH and β-EP, have distinct roles in this process. α-MSH inhibits food intake, whereas β-EP, an endogenous opioid, can inhibit POMC neurons and stimulate food intake. A mouse model was used to examine the effects of opioid antagonism with naltrexone (NTX) on Pomc and Agrp gene expression and POMC peptide processing in the hypothalamus in conjunction with changes in energy balance. There were clear stimulatory effects of NTX on hypothalamic Pomc in mice receiving low- and high-fat diets, yet only transient decreases in food intake and body weight gain were noted. The effects on Pomc expression were accompanied by an increase in POMC prohormone levels and a decrease in levels of the processed peptides α-MSH and β-EP. Arcuate expression of the POMC processing enzymes Pcsk1, Pcsk2, and Cpe was not altered by NTX, but expression of Prcp, an enzyme that inactivates α-MSH, increased after NTX exposure. NTX exposure also stimulated hypothalamic Agrp expression, but the effects of NTX on energy balance were not enhanced in Agrp-null mice. Despite clear stimulatory effects of NTX on Pomc expression in the hypothalamus, only modest transient decreases in food intake and body weight were seen. Effects of NTX on POMC processing, and possibly α-MSH inactivation, as well as stimulatory effects on AgRP neurons could mitigate the effects of NTX on energy balance.

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Chou, Chia-Lin, Tzu-Ju Chen, Cheng-Yi Lin, Sung-Wei Lee, Shih-Chang Wang, Shou-Sheng Chu, and Ching-Chieh Yang. "PCSK1 Overexpression in Rectal Cancer Correlates with Poor Response to Preoperative Chemoradiotherapy and Prognosis." OncoTargets and Therapy Volume 13 (April 2020): 3141–50. http://dx.doi.org/10.2147/ott.s243750.

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Kilpelainen, T. O., S. A. Bingham, K. T. Khaw, N. J. Wareham, and R. J. F. Loos. "Association of variants in the PCSK1 gene with obesity in the EPIC-Norfolk study." Human Molecular Genetics 18, no. 18 (June 15, 2009): 3496–501. http://dx.doi.org/10.1093/hmg/ddp280.

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Qi, Qibin, Huaixing Li, Ruth J. F. Loos, Chen Liu, Frank B. Hu, Hongyu Wu, Zhijie Yu, and Xu Lin. "Association of PCSK1 rs6234 with Obesity and Related Traits in a Chinese Han Population." PLoS ONE 5, no. 5 (May 17, 2010): e10590. http://dx.doi.org/10.1371/journal.pone.0010590.

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Philippe, J., P. Stijnen, D. Meyre, F. De Graeve, D. Thuillier, J. Delplanque, G. Gyapay, et al. "A nonsense loss-of-function mutation in PCSK1 contributes to dominantly inherited human obesity." International Journal of Obesity 39, no. 2 (June 3, 2014): 295–302. http://dx.doi.org/10.1038/ijo.2014.96.

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CHEN, JIE, MEI YANG, KEHUI ZHAO, AIMIN XU, and QINGYANG HUANG. "Polymorphisms in FTO, TMEM18 and PCSK1 are associated with BMI in southern Chinese population." Journal of Genetics 93, no. 2 (August 2014): 509–12. http://dx.doi.org/10.1007/s12041-014-0384-x.

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Seidah, Nabil G., Antonella Pasquato, and Ursula Andréo. "How Do Enveloped Viruses Exploit the Secretory Proprotein Convertases to Regulate Infectivity and Spread?" Viruses 13, no. 7 (June 25, 2021): 1229. http://dx.doi.org/10.3390/v13071229.

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Inhibition of the binding of enveloped viruses surface glycoproteins to host cell receptor(s) is a major target of vaccines and constitutes an efficient strategy to block viral entry and infection of various host cells and tissues. Cellular entry usually requires the fusion of the viral envelope with host plasma membranes. Such entry mechanism is often preceded by “priming” and/or “activation” steps requiring limited proteolysis of the viral surface glycoprotein to expose a fusogenic domain for efficient membrane juxtapositions. The 9-membered family of Proprotein Convertases related to Subtilisin/Kexin (PCSK) serine proteases (PC1, PC2, Furin, PC4, PC5, PACE4, PC7, SKI-1/S1P, and PCSK9) participate in post-translational cleavages and/or regulation of multiple secretory proteins. The type-I membrane-bound Furin and SKI-1/S1P are the major convertases responsible for the processing of surface glycoproteins of enveloped viruses. Stefan Kunz has considerably contributed to define the role of SKI-1/S1P in the activation of arenaviruses causing hemorrhagic fever. Furin was recently implicated in the activation of the spike S-protein of SARS-CoV-2 and Furin-inhibitors are being tested as antivirals in COVID-19. Other members of the PCSK-family are also implicated in some viral infections, such as PCSK9 in Dengue. Herein, we summarize the various functions of the PCSKs and present arguments whereby their inhibition could represent a powerful arsenal to limit viral infections causing the present and future pandemics.

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Ahmed, Amna Basheer M., and Badr M. Rasheed Alsaleem. "Enteroendocrine Dysfunction in Two Saudi Sisters." Case Reports in Gastroenterology 15, no. 1 (March 4, 2021): 290–95. http://dx.doi.org/10.1159/000511761.

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Proprotein convertase (PC) deficiency is a rare autosomal recessive disorder caused by mutations in proprotein convertase subtilisin/kexin type 1 (<i>PCSK1</i>). It is characterized by severe malabsorptive early-onset diarrhea, obesity, and systemic endocrinopathies. Only few cases have been reported in the literature; we have add two female sisters with some difference in clinical progress. Herein, we describe two sisters with congenital osmotic diarrhea diagnosed with PC1/3 deficiency, causing malabsorptive diarrhea and enteroendocrine dysfunction, who presented with chronic enteropathy with hypernatremia but with different expressivity. PC1/3 deficiency presents with symptoms and signs that mimic glucose-galactose malabsorption. Because of the clinical paucity and heterogeneity of congenital enteropathies, whole-exome sequencing may be of great help towards early diagnosis and effective treatment.

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Choi, Seungbum, Aleksandra Aljakna, and Ron Korstanje. "GW28-e0704 PCSK1 MUTANT MICE DISPLAY INCREASED APOA1 LEVEL AND DECREASED PLTP ACTIVITIY IN SERUM." Journal of the American College of Cardiology 70, no. 16 (October 2017): C64—C65. http://dx.doi.org/10.1016/j.jacc.2017.07.220.

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Stijnen, Pieter, Krizia Tuand, Tibor V. Varga, Paul W. Franks, Bert Aertgeerts, and John W. M. Creemers. "The Association of Common Variants in PCSK1 With Obesity: A HuGE Review and Meta-Analysis." American Journal of Epidemiology 180, no. 11 (October 29, 2014): 1051–65. http://dx.doi.org/10.1093/aje/kwu237.

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Villalobos-Comparán, Marisela, Hugo Villamil-Ramírez, Teresa Villarreal-Molina, Elena Larrieta-Carrasco, Paola León-Mimila, Sandra Romero-Hidalgo, Leonor Jacobo-Albavera, et al. "PCSK1 rs6232 Is Associated with Childhood and Adult Class III Obesity in the Mexican Population." PLoS ONE 7, no. 6 (June 21, 2012): e39037. http://dx.doi.org/10.1371/journal.pone.0039037.

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Argente, J., S. Farooqi, E. Van Den Akker, S. Malhotra, P. Kühnen, K. Clément, and M. Wabitsch. "Caractéristiques cliniques des porteurs de variants sur les gènes POMC, PCSK1, LEPR, NCOA1 et SH2B1." Annales d'Endocrinologie 84, no. 5 (October 2023): 669. http://dx.doi.org/10.1016/j.ando.2023.07.467.

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Chetty, K., A. Khathi, S. Schneider, and Gerda Martha Marx. "Type 2 Diabetes Mellitus Serum Biomarker Levels and Associated Single Nucleotide Polymorphisms in a South African Population." Series of Endocrinology, Diabetes and Metabolism 5, no. 3 (October 12, 2023): 100–118. http://dx.doi.org/10.54178/jsedmv5i3001.

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Type 2 diabetes mellitus (T2DM) is a metabolic disorder with multiple causes. The prevalence of T2DM is on the rise, however, on the African continent, nearly 70% of all T2DM cases go undiagnosed. T2DM places a great burden on the already stretched healthcare systems. Current tests do not provide predictive measures in terms of the possible onset of the disease. Biomarker and gene analysis have been used to predict the onset of the disease, but this has seen very limited use in the African population groups. Identification of variances in biomarkers and subsequent genetic aberrations at early diagnosis could enable clinical focus on patients more likely to develop insulin resistance. The aim of the study was to compare T2DM-associated biomarker levels between T2DM patients and non-T2DM participants and identify genetic variances in single nucleotide polymorphisms (SNPs) associated with the biomarkers. Two cohorts (n = 78) were screened for associated biomarkers using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. The results of this analysis were used to select SNPs in genes associated with the screened biomarkers. The molecular genotyping was completed using quantitative polymerase chain reaction (qPCR) assays. The biomarker analysis revealed significant statistical differences between four of the ten screened biomarkers: Glucose-dependent insulinotropic polypeptide (GIP) (p = 0.0004), resistin (p = 0.0398), visfatin (p = 0.0009), and glucagon (p = 0.0034). The SNPs selected for molecular genotyping were rs6235 in proprotein convertase subtilisin/kexin type 1 (PCSK1) and rs2208203 in proprotein convertase subtilisin/kexin type 2 (PCSK2). Both these genes are involved in the biosynthesis of various biomarkers that were screened. The results from the molecular genotyping failed to show any significant difference between the control and T2DM case groups. While some biomarkers were shown to have significant statistical differences between the two study cohorts, more work needs to be conducted to understand the role of each biomarker in T2DM.

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TAYLOR, AUSTIN, YI-CHUN CHEN, DANIEL PASULA, DAN S. LUCIANI, and BRUCE VERCHERE. "123-OR: Deletion of Both Pcsk1 And Pcsk2 in Beta Cells: Lack of Mature Insulin Drives Beta-Cell Expansion and Dysfunction, but Not Severe Diabetes in Mice." Diabetes 70, Supplement 1 (June 2021): 123—OR. http://dx.doi.org/10.2337/db21-123-or.

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