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

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.

• Authors: Kishan Kumar Chudasama, Jonathon Winnay, Stefan Johansson, Tor Claudi, Rainer König, Ingfrid Haldorsen, Bente Johansson, Ju Rang Woo, Dagfinn Aarskog, Jørn V Sagen, C Ronald Kahn, Anders Molven, Pål Rasmus Njølstad
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 93 Issue 1 Pg. 150-7 (Jul 11 2013) ISSN: 1537-6605 [Electronic] United States
• PMID: 23810379 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• Adipocytes (metabolism)
• Adolescent
• Adult
• Aged
• Amino Acid Sequence
• Body Mass Index
• Cell Differentiation
• Class Ia Phosphatidylinositol 3-Kinase (genetics, 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, pathology)
• Humans
• Hypercalcemia (enzymology, pathology)
• Insulin Receptor Substrate Proteins (genetics, metabolism)
• Male
• Metabolic Diseases (enzymology, pathology)
• Middle Aged
• Molecular Sequence Data
• Mutation
• Nephrocalcinosis (enzymology, pathology)
• Pedigree
• Signal Transduction
• Young Adult
• src Homology Domains