title: PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders.
abstract: 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.
authors.affiliation: Laboratory for Biochemical Neuroendocrinology (P.S., B.R.-M., J.W.M.C.), Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; and Medical Research Council (MRC) Metabolic Diseases Unit (S.O.), Wellcome Trust-MRC Institute of Metabolic Science, National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Pieter
authors.initials: P
authors.lastname: Stijnen
authors.affiliation: Laboratory for Biochemical Neuroendocrinology (P.S., B.R.-M., J.W.M.C.), Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; and Medical Research Council (MRC) Metabolic Diseases Unit (S.O.), Wellcome Trust-MRC Institute of Metabolic Science, National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ramos-Molina
authors.affiliation: Laboratory for Biochemical Neuroendocrinology (P.S., B.R.-M., J.W.M.C.), Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; and Medical Research Council (MRC) Metabolic Diseases Unit (S.O.), Wellcome Trust-MRC Institute of Metabolic Science, National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.affiliation: Laboratory for Biochemical Neuroendocrinology (P.S., B.R.-M., J.W.M.C.), Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; and Medical Research Council (MRC) Metabolic Diseases Unit (S.O.), Wellcome Trust-MRC Institute of Metabolic Science, National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
authors.forename: John W M
authors.initials: JW
authors.lastname: Creemers
mesh_terms: D000818:Animals; D004700:Endocrine System Diseases / Q000378:metabolism*; D005767:Gastrointestinal Diseases / Q000378:metabolism*; D006801:Humans; D009765:Obesity / Q000378:metabolism*; D045664:Proprotein Convertase 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
chemical_list: C587576:PCSK1 protein, human; D045664:Proprotein Convertase 1