Mutation of IGFBP7 causes upregulation of BRAF/MEK/ERK pathway and familial retinal arterial macroaneurysms |
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| Authors: | Abu-Safieh Leen Abboud Emad B Alkuraya Hisham Shamseldin Hanan Al-Enzi Shamsa Al-Abdi Lama Hashem Mais Colak Dilek Jarallah Abdullah Ahmad Hala Bobis Steve Nemer Georges Bitar Fadi Alkuraya Fowzan S |
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| Institution: | 1Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia;2Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh 11462, Saudi Arabia;3Department of Biostatistics, Epidemiology and Computing, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia;4Department of Cardiac Sciences, King Khalid University Hospital and College of Medicine, Riyadh 11462, Saudi Arabia;5Department of Comparative Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia;6Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut 1107 2020, Lebanon;7Department of Pediatrics, American University of Beirut, Beirut 1107 2020, Lebanon;8Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia;9Department of Pediatrics, King Khalid University Hospital and College of Medicine, Riyadh 11462, Saudi Arabia |
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| Abstract: | 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. |
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