SHORT Syndrome with Partial Lipodystrophy Due to Impaired Phosphatidylinositol 3 Kinase Signaling
SHORT Syndrome with Partial Lipodystrophy Due to Impaired Phosphatidylinositol 3 Kinase Signaling
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DOI：
10.1016/j.ajhg.2013.05.023
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发表时间：
2013-07-11
影响因子：
9.8
通讯作者：
Njolstad, Pal Rasmus
中科院分区：
文献类型：
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作者：
Chudasama, Kishan Kumar;Winnay, Jonathon;Njolstad, Pal Rasmus
磷脂酰肌醇3激酶（PI 3 K）途径调节基本的细胞过程，例如代谢、增殖和存活。该途径中的中心组分是p85 α，由PIK 3R 1编码的调节亚基。使用全外显子组测序，我们在两个受部分脂肪营养不良、低体重指数、身材矮小、早老性面容和Rieger异常（SHORT综合征）影响的不相关家族中发现了杂合PIK 3R 1突变（c.1945C>T [p.Arg649Trp]）。这种突变导致p85 α和IRS-1之间的相互作用受损，并减少了受影响受试者的成纤维细胞和重建的Pik 3r 1敲除前脂肪细胞中AKT介导的胰岛素信号传导。正常的PI 3 K活性对于脂肪分化和胰岛素信号传导至关重要;因此，突变的PIK 3R 1在脂肪代谢障碍、生长和胰岛素信号传导之间提供了独特的联系。
The phosphatidylinositol 3 kinase (PI3K) pathway regulates fundamental cellular processes such as metabolism, proliferation, and survival. A central component in this pathway is the p85 alpha, 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 p85 alpha 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.