Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort

Martin Grangeio, Monica; Lindberg, Iris; Solorzano-Vargas, R. Sergio; Wang, Jiafang; Avitzur, Yaron; Bandsma, Robert; Sokollik, Christiane; Lawrence, Sarah; Pickett, Lindsay A.; Chen, Zijun; Egritas, Odul; Dalgic, Buket; Albornoz, Valeria; de Ridder, Lissy; Hulst, Jessie; Gok, Faysal; Aydoğan, Ayşen; Al-Hussaini, Abdulrahman; Gok, Deniz Engin; Yourshaw, Michael; ... (2013). Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. Gastroenterology, 145(1), pp. 138-148. Elsevier 10.1053/j.gastro.2013.03.048

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BACKGROUND & AIMS Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal-recessive disorder caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 also have been associated with obesity in heterozygotes in several population-based studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency. METHODS We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins. RESULTS We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears. CONCLUSIONS In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in the processing of one or more enteric hormones that are required for nutrient absorption.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine > Paediatric Gastroenterology

UniBE Contributor:

Martin Grangeio, Monica and Sokollik, Christiane

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0016-5085

Publisher:

Elsevier

Language:

English

Submitter:

Christiane Sokollik

Date Deposited:

12 Jun 2014 10:38

Last Modified:

12 Jun 2014 10:38

Publisher DOI:

10.1053/j.gastro.2013.03.048

PubMed ID:

23562752

URI:

https://boris.unibe.ch/id/eprint/45615

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