Severe obesity and diabetes insipidus in a patient with PCSK1 deficiency

Frank, Graeme R.; Fox, Joyce; Candela, Ninfa; Jovanović, Zorica; Bochukova, Elena G.; Levine, Jeremiah; Papenhausen, Peter; O’Rahilly, Stephen; Farooqi, I. Sadaf

doi:10.1016/j.ymgme.2013.04.005

Cited by 64 publications

(38 citation statements)

References 15 publications

(6 reference statements)

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“…No evidence of male hypogonadism was described in six other infants. The treatment of one male patient with micropenis with monthly testosterone injections for 3 months resulted in the normalization of his penis size (87,88,90).…”

Section: Hypogonadotropic Hypogonadismmentioning

confidence: 99%

“…Proinsulin has reduced affinity for its receptor but an increased half-life (84), which is the likely explanation for the postprandial hypoglycemia observed in this patient. Three additional patients have since been identified by the same group, one of which was homozygous and the other two combined heterozygous for deleterious mutations in PCSK1 (85)(86)(87). Since these patients exhibited features of intestinal malabsorption, the early clinical history of the first PC1/3 null patient was re-evaluated, revealing that in the first decade of life, despite severe obesity, she also suffered from frequent diarrhea and was investigated by intestinal biopsy because of clinical suspicion of celiac disease.…”

Section: A Clinical Aspects Of Pcsk1 Deficiencymentioning

confidence: 99%

“…She became pregnant (with quadruplets) after the administration of gonadotropins to induce ovulation (82). Since then six other different cases of hypogonadism have been reported in infants, five boys with micropenis and one girl with delayed puberty (87,88,90). No evidence of male hypogonadism was described in six other infants.…”

Section: Hypogonadotropic Hypogonadismmentioning

confidence: 99%

“…Interestingly, however, in a recent meta-analysis, Nead et al identified the single nucleotide polymorphisms (SNPs) rs6234-rs6235 to be significantly associated with reduced body length (95). Diabetes insipidus has been reported in a subset of PC1/3 null patients (85)(86)(87)(88).…”

Section: Hypothyroidism Hypocortisolism Growth Hormone (Gh) Deficiementioning

confidence: 99%

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PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders

et al. 2016

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Prohormone convertase 1/3, encoded by the PCSK1 gene, is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones. Humans who are homozygous or compound heterozygous for loss-of-function mutations in PCSK1 exhibit a variable and pleiotropic syndrome consisting of some or all of the following: obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function, and impaired regulation of plasma glucose levels in association with elevated circulating proinsulin-to-insulin ratio. Recently, more common variants in the PCSK1 gene have been found to be associated with alterations in body mass index, increased circulating proinsulin levels, and defects in glucose homeostasis. This review provides an overview of the endocrinopathies and other disorders observed in prohormone convertase 1/3-deficient patients, discusses the possible biochemical basis for these manifestations of the disease, and proposes a model whereby certain missense mutations in PCSK1 may result in proteins with a dominant negative action.

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Section: Hypogonadotropic Hypogonadismmentioning

confidence: 99%

Section: A Clinical Aspects Of Pcsk1 Deficiencymentioning

confidence: 99%

Section: Hypogonadotropic Hypogonadismmentioning

confidence: 99%

Section: Hypothyroidism Hypocortisolism Growth Hormone (Gh) Deficiementioning

confidence: 99%

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PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders

et al. 2016

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“…Since body weight is sensitive to changes in the concentration of POMC-derived peptides [22][23][24][25][26] , understanding POMC processing can provide insights into molecular mechanisms of obesity that might be therapeutically harnessed 3 . Indeed, obesity results from the reduced functionality of the POMC-processing enzymes proprotein convertase subtilisin/kexin type 1 (PCSK1, PC1/3) 27,28 , carboxypeptidase E (CPE) 29,30 , or the transcription factor nescient helix-loop-helix 2 (NHLH2) that regulates PCSK1 expression 31,32 . Since POMC processing is incomplete even in wild-type brains 9,10 , stimulating POMC production or promoting its processing might reduce body weight in obesity.…”

Section: Introductionmentioning

confidence: 99%

Human POMC processing in vitro and in vivo revealed by quantitative peptidomics

Kirwan

Kay

Brouwers

et al. 2018

Preprint

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Human obesity can result from the aberrant production or processing of proopiomelanocortin (POMC) in hypothalamic neurons, but it is unclear which human POMC-derived peptides are most relevant to body weight regulation. To address this question, we analysed both hypothalamic neurons derived from human pluripotent stem cells (hPSCs) and primary human hypothalamic tissue using quantitative liquid chromatography tandem mass spectroscopy (LC-MS/MS). In both in vitro-and in vivo-derived samples, we found that POMC was processed into b-melanocyte stimulating hormone (b-MSH), whose existence in the human brain has been controversial. b-MSH and desacetyl a-MSH (d-a-MSH) were produced at roughly equimolar concentrations and in vast excess to acetylated a-MSH (5-to 200-fold), suggesting that the importance of both d-a-MSH and b-MSH to human obesity has been underestimated. Since body weight is sensitive to changes in MSH concentration, we asked whether hPSC-derived hypothalamic neurons could provide mechanistic insights into the processing and secretion of MSH peptides. We found that cultured human hypothalamic neurons appropriately trafficked POMC and its derivatives, and robustly (P<0.0001) secreted them when depolarised. Furthermore, the adipocyte-derived hormone leptin significantly (P<0.01) promoted their production of both d-a-MSH and b-MSH. These results establish hPSC-derived hypothalamic neurons as a model system for studying human-specific aspects of POMC processing that might be therapeutically harnessed to treat obesity.

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Novel LEPR mutations in obese Pakistani children identified by PCR‐based enrichment and next generation sequencing

Saeed

Bonnefond

Manzoor

et al. 2013

Obesity

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Objective: Mutations in leptin receptor gene (LEPR) result in early onset extreme adiposity. However, their prevalence in different populations is not known. Indeed, LEPR screening by gold standard Sanger sequencing has been limited by its large size and the cost. One-step PCR-based targeted enrichment could be an option for rapid and cost effective molecular diagnosis of monogenic forms of obesity. Methods: The study is based on 39 unrelated severely obese Pakistani children, previously shown to be negative for leptin (LEP) and melanocortin 4 receptor (MC4R) gene mutations, from an initial cohort of 62 probands. Patient samples were analyzed by microdroplet PCR-enrichment (RainDance technologies) targeting coding exons of 26 obesity-associated genes combined with next generation sequencing. Hormone levels were analyzed by ELISA. Results: The analysis revealed two novel homozygous LEPR mutations, an essential splice site mutation in exon 15 (c.2396-1 G>T), and a nonsense mutation in exon 10 (c.1675 G>A). Both probands had high leptin levels and were phenotypically indistinguishable from age-matched leptin-deficient subjects from the same population. Conclusions: The two subjects carrying homozygous LEPR mutations, reported here for the first time in the Pakistani population, constitute 3% of the whole cohort of severely obese children (compared to 17% for LEP and 3% for MC4R).

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Severe obesity and diabetes insipidus in a patient with PCSK1 deficiency

Cited by 64 publications

References 15 publications

PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders

PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders

Human POMC processing in vitro and in vivo revealed by quantitative peptidomics

Novel LEPR mutations in obese Pakistani children identified by PCR‐based enrichment and next generation sequencing

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