title: A novel familial mutation in the PCSK1 gene that alters the oxyanion hole residue of proprotein convertase 1/3 and impairs its enzymatic activity.
abstract: Four siblings presented with congenital diarrhea and various endocrinopathies. Exome sequencing and homozygosity mapping identified five regions, comprising 337 protein-coding genes that were shared by three affected siblings. Exome sequencing identified a novel homozygous N309K mutation in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, encoding the neuroendocrine convertase 1 precursor (PC1/3) which was recently reported as a cause of Congenital Diarrhea Disorder (CDD). The PCSK1 mutation affected the oxyanion hole transition state-stabilizing amino acid within the active site, which is critical for appropriate proprotein maturation and enzyme activity. Unexpectedly, the N309K mutant protein exhibited normal, though slowed, prodomain removal and was secreted from both HEK293 and Neuro2A cells. However, the secreted enzyme showed no catalytic activity, and was not processed into the 66 kDa form. We conclude that the N309K enzyme is able to cleave its own propeptide but is catalytically inert against in trans substrates, and that this variant accounts for the enteric and systemic endocrinopathies seen in this large consanguineous kindred.
authors.affiliation: Gastroenterology Unit, Division of Pediatrics, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Wilschanski
authors.affiliation: Gastroenterology Unit, Division of Pediatrics, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Montaser
authors.initials: M
authors.lastname: Abbasi
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland-Baltimore, Baltimore, Maryland, United States of America; Department of Pediatrics, Division of Gastroenterology and Nutrition, Mattel Children's Hospital and the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Elias
authors.initials: E
authors.lastname: Blanco
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland-Baltimore, Baltimore, Maryland, United States of America.
authors.forename: Iris
authors.initials: I
authors.lastname: Lindberg
authors.affiliation: Department of Pediatrics, Division of Gastroenterology and Nutrition, Mattel Children's Hospital and the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Yourshaw
authors.affiliation: Endocrinology Unit, Division of Pediatrics, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Zangen
authors.affiliation: Neurology Unit, Division of Pediatrics, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Itai
authors.initials: I
authors.lastname: Berger
authors.affiliation: Gastroenterology Unit, Division of Pediatrics, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Shteyer
authors.affiliation: Department of Pathology, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Pappo
authors.affiliation: Department of Neonatology, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bar-Oz
authors.affiliation: Department of Pediatrics, Division of Gastroenterology and Nutrition, Mattel Children's Hospital and the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Martín
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
mesh_terms: D002648:Child; D003967:Diarrhea / Q000151:congenital* / Q000235:genetics* / Q000378:metabolism; D004700:Endocrine System Diseases / Q000235:genetics / Q000378:metabolism; D059472:Exome; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010375:Pedigree; D045664:Proprotein Convertase 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: C587576:PCSK1 protein, human; D045664:Proprotein Convertase 1