SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling

Am J Hum Genet. 2013 Jul 11;93(1):150-7. doi: 10.1016/j.ajhg.2013.05.023. Epub 2013 Jun 27.

Abstract

The phosphatidylinositol 3 kinase (PI3K) pathway regulates fundamental cellular processes such as metabolism, proliferation, and survival. A central component in this pathway is the p85α regulatory subunit, encoded by PIK3R1. Using whole-exome sequencing, we identified a heterozygous PIK3R1 mutation (c.1945C>T [p.Arg649Trp]) in two unrelated families affected by partial lipodystrophy, low body mass index, short stature, progeroid face, and Rieger anomaly (SHORT syndrome). This mutation led to impaired interaction between p85α and IRS-1 and reduced AKT-mediated insulin signaling in fibroblasts from affected subjects and in reconstituted Pik3r1-knockout preadipocytes. Normal PI3K activity is critical for adipose differentiation and insulin signaling; the mutated PIK3R1 therefore provides a unique link among lipodystrophy, growth, and insulin signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Adolescent
  • Adult
  • Aged
  • Amino Acid Sequence
  • Body Mass Index
  • Cell Differentiation
  • Class Ia Phosphatidylinositol 3-Kinase / genetics
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism*
  • DNA Mutational Analysis
  • Enzyme Activation
  • Exome
  • Female
  • Fibroblasts / metabolism
  • Gene Knockout Techniques
  • Genetic Carrier Screening
  • Genetic Predisposition to Disease
  • Genetics, Population / methods
  • Growth Disorders / enzymology*
  • Growth Disorders / pathology
  • Humans
  • Hypercalcemia / enzymology*
  • Hypercalcemia / pathology
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Male
  • Metabolic Diseases / enzymology*
  • Metabolic Diseases / pathology
  • Middle Aged
  • Molecular Sequence Data
  • Mutation
  • Nephrocalcinosis / enzymology*
  • Nephrocalcinosis / pathology
  • Pedigree
  • Signal Transduction*
  • Young Adult
  • src Homology Domains

Substances

  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Class Ia Phosphatidylinositol 3-Kinase

Supplementary concepts

  • SHORT syndrome