title: Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Martín G
authors.initials: MG
authors.lastname: Martín
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland-Baltimore, Baltimore, Maryland.
authors.forename: Iris
authors.initials: I
authors.lastname: Lindberg
authors.affiliation: 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.
authors.forename: R Sergio
authors.initials: RS
authors.lastname: Solorzano-Vargas
authors.affiliation: 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.
authors.forename: Jiafang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Avitzur
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Bandsma
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christiane
authors.initials: C
authors.lastname: Sokollik
authors.affiliation: Division of Endocrinology and Metabolism, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lawrence
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland-Baltimore, Baltimore, Maryland.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Pickett
authors.affiliation: 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.
authors.forename: Zijun
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Gazi University School of Medicine, Department of Pediatric Gastroenterology, Ankara, Turkey.
authors.forename: Odul
authors.initials: O
authors.lastname: Egritas
authors.affiliation: Gazi University School of Medicine, Department of Pediatric Gastroenterology, Ankara, Turkey.
authors.forename: Buket
authors.initials: B
authors.lastname: Dalgic
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland-Baltimore, Baltimore, Maryland.
authors.forename: Valeria
authors.initials: V
authors.lastname: Albornoz
authors.affiliation: Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Lissy
authors.initials: L
authors.lastname: de Ridder
authors.affiliation: Pediatric Gastroenterology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Jessie
authors.initials: J
authors.lastname: Hulst
authors.affiliation: Department of Pediatrics Nephrology, Gulhane Military Medical Academy School of Medicine, Ankara, Turkey.
authors.forename: Faysal
authors.initials: F
authors.lastname: Gok
authors.affiliation: Department of Pediatric Gastroenterology Hepatology and Nutrition, Kocaeli University Faculty of Medicine, Kocaeli, Turkey.
authors.forename: Ayşen
authors.initials: A
authors.lastname: Aydoğan
authors.affiliation: Pediatric Gastroenterology and Hepatology, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Al-Hussaini
authors.affiliation: Department of Endocrinology, Gulhane Military Medical Academy School of Medicine, Ankara, Turkey.
authors.forename: Deniz Engin
authors.initials: DE
authors.lastname: Gok
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Yourshaw
authors.affiliation: VA Greater Los Angeles Healthcare System, Los Angeles, California.
authors.forename: S Vincent
authors.initials: SV
authors.lastname: Wu
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Galen
authors.initials: G
authors.lastname: Cortina
authors.affiliation: 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.
authors.forename: Sara
authors.initials: S
authors.lastname: Stanford
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Senta
authors.initials: S
authors.lastname: Georgia
mesh_terms: D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000097:blood; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003967:Diarrhea / Q000209:etiology*; D004700:Endocrine System Diseases / Q000150:complications / Q000151:congenital / Q000209:etiology*; D005260:Female; D006801:Humans; D007223:Infant; D008286:Malabsorption Syndromes / Q000209:etiology*; D008297:Male; D009154:Mutation; D009765:Obesity / Q000150:complications* / Q000151:congenital; D045664:Proprotein Convertase 1 / Q000172:deficiency* / Q000235:genetics
chemical_list: D000324:Adrenocorticotropic Hormone; D045664:Proprotein Convertase 1
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