Mutation in the SH2 domain of PIK3R1 cause SHORT syndrome with partial lipodystrophy. S. Johansson1,2, K. K. Chudasama1,2, J. Winnay3, T. Claudi4, R. König5, I. Haldorsen6, B. Johansson1, J. R. Woo3, D. Aarskog1, J. V. Sagen1, C. R. Kahn3, A. Molven6, P. R. Njolstad1,7 1) KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; 2) Center for Med Genet and Mol Medic, Haukeland Univ Hosp, Bergen, Norway; 3) Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA; 4) Department of Medicine, Nordlandssykehuset, N-8092, Bodř, Norway; 5) Department of Human Genetics, University of Frankfurt, G-60325, Frankfurt, Germany; 6) Department of Clinical Medicine, University of Bergen, Bergen, Norway; 7) Department of Pediatrics, Haukeland University Hospital, N-5021, Bergen, Norway.

   SHORT syndrome (OMIM #269880) is characterized by Short stature, Hyperextensibility of joints, Ocular depression, Rieger anomaly and Teething delay as well as partial lipodystrophy and facial dysmorphic features. Until now, the genetic cause of SHORT syndrome has been unknown. We studied two unrelated families with short stature, ocular depression, Rieger anomaly, partial lipodystrophy and progeroid face. Although they had partial lipodystrophy, serum cholesterol and triglyceride levels were within the normal range. Moreover, serum alanine transaminase and -glutamyltransferase were normal, and abdominal computer tomography scans showed no sign of hepatic steatosis. Using whole-exome sequencing, we identified the same heterozygous PIK3R1 mutation (c.1945C>T corresponding to p.Arg649Trp) as the cause of the disorder in both families. PIK3R1 encodes p85, a regulatory subunit of the phosphatidylinositol (PI) 3-kinase signaling pathway, which is critical for fundamental cellular processes such as metabolism, proliferation and survival. The mutation led to impaired interaction of p85alpha with IRS-1 and reduced AKT-mediated insulin signaling in patient fibroblasts and in reconstituted Pik3r1 knockout pre-adipocytes. Results from transgenic mice expressing the mutant protein will be presented at the meeting. Normal PI 3-kinase activity is critical for adipose differentiation and insulin signaling; the mutation in PIK3R1 therefore provides a unique link between lipodystrophy, growth and insulin signaling, adding new possibilities for diagnosis and targeted treatment in these diseases.

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