PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders

Endocr Rev. 2016 Aug;37(4):347-71. doi: 10.1210/er.2015-1117. Epub 2016 May 17.

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.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endocrine System Diseases / metabolism*
  • Gastrointestinal Diseases / metabolism*
  • Humans
  • Obesity / metabolism*
  • Proprotein Convertase 1 / deficiency*
  • Proprotein Convertase 1 / genetics
  • Proprotein Convertase 1 / metabolism*

Substances

  • PCSK1 protein, human
  • Proprotein Convertase 1