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

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

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1
K.G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020 Bergen, Norway.

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.

PMID:
23810379
PMCID:
PMC3710758
DOI:
10.1016/j.ajhg.2013.05.023
[Indexed for MEDLINE]
Free PMC Article
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