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

Gastroenterology. 2013 Jul;145(1):138-148. doi: 10.1053/j.gastro.2013.03.048.

Martín G Martín ¹, Iris Lindberg ², R Sergio Solorzano-Vargas ³, Jiafang Wang ³, Yaron Avitzur ⁴, Robert Bandsma ⁴, Christiane Sokollik ⁴, Sarah Lawrence ⁵, Lindsay A Pickett ², Zijun Chen ³, Odul Egritas ⁶, Buket Dalgic ⁶, Valeria Albornoz ², Lissy de Ridder ⁷, Jessie Hulst ⁷, Faysal Gok ⁸, Ayşen Aydoğan ⁹, Abdulrahman Al-Hussaini ¹⁰, Deniz Engin Gok ¹¹, Michael Yourshaw ¹², S Vincent Wu ¹³, Galen Cortina ¹⁴, Sara Stanford ³, Senta Georgia ¹⁵

Affiliations

1 Department of Pediatrics, Division of Gastroenterology and Nutrition, Mattel Children's Hospital, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. Electronic address: mmartin@mednet.ucla.edu.
2 Department of Anatomy and Neurobiology, University of Maryland-Baltimore, Baltimore, Maryland.
3 Department of Pediatrics, Division of Gastroenterology and Nutrition, Mattel Children's Hospital, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
4 Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
5 Division of Endocrinology and Metabolism, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
6 Gazi University School of Medicine, Department of Pediatric Gastroenterology, Ankara, Turkey.
7 Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
8 Department of Pediatrics Nephrology, Gulhane Military Medical Academy School of Medicine, Ankara, Turkey.
9 Department of Pediatric Gastroenterology Hepatology and Nutrition, Kocaeli University Faculty of Medicine, Kocaeli, Turkey.
10 Pediatric Gastroenterology and Hepatology, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
11 Department of Endocrinology, Gulhane Military Medical Academy School of Medicine, Ankara, Turkey.
12 Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
13 VA Greater Los Angeles Healthcare System, Los Angeles, California.
14 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
15 Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

PMID: 23562752 DOI: 10.1053/j.gastro.2013.03.048

Abstract

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.

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