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.
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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)
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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
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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
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