Mutation of IGFBP7 Causes Upregulation of BRAF/MEK/ERK Pathway and Familial Retinal Arterial Macroaneurysms

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• 作者：Leen Abu-Safieh¹ ; ¹⁰ ; Emad B. Abboud² ; ¹⁰ ; Hisham Alkuraya¹ ; ² ; ¹⁰ ; Hanan Shamseldin¹ ; Shamsa Al-Enzi¹ ; Lama Al-Abdi¹ ; Mais Hashem¹ ; Dilek Colak³ ; Abdullah Jarallah⁴ ; Hala Ahmad⁵ ; Steve Bobis⁵ ; Georges Nemer⁶ ; Fadi Bitar⁷ ; Fowzan  ; S. Alkuraya¹ ; ⁸ ; ⁹ ; ^{falkuraya@kfshrc.edu.sa"" rel=""nofollow}
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：12 August 2011
• 年：2011
• 卷：89
• 期：2
• 页码：313-319
• 全文大小：1003 K

文摘

Insulin-like growth factor binding proteins (IGFBPs) play important physiological functions through the modulation of IGF signaling as well as IGF-independent mechanisms. Despite the established role of IGFs in development, a similar role for the seven known IGFBPs has not been established in humans. Here, we show that an autosomal-recessive syndrome that consists of progressive retinal arterial macroaneurysms and supravalvular pulmonic stenosis is caused by mutation of IGFBP7. Consistent with the recently established inhibitory role of IGFBP7 on BRAF signaling, the BRAF/MEK/ERK pathway is upregulated in these patients, which may explain why the cardiac phenotype overlaps with other disorders characterized by germline mutations in this pathway. The retinal phenotype appears to be mediated by a role in vascular endothelium, where IGFBP7 is highly expressed.