Recurrent Mutation in IGFPB7 Causes Upregulation of Raf Ras MEK ERK Pathway and Familial Retinal Artery Macroaneurysm

Abstract

Purpose: : Aim of this study is to identify the genetic defect that causes the novel Familial Retinal Artery Macroaneurysm or FRAM.

Methods: : Linkage analysis and homozygosity mapping using the 250K affymetrix chip were used to map the loci for FRAM in 5 consanguineous families. Direct sequencing of genes in the critical genetic interval resulted in identifying the disease causing gene in the IGFBP7. Western blot analysis and insitu experiments were further used to confirm the effect of the mutation on the proteint level and establish the expression pattern of the gene in mouse emberyos.

Results: : Splicing mutation in IGFBP7 is found to be cuasing the novel FRAM phenotype.

Conclusions: : Insulin-like growth factor binding proteins (IGFBP) 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 by the seven known IGFBPs has not been established in humans. Here, we show that an autosomal recessive syndrome that consists of progressive retinal artery macroaneurysms and supravalvular pulmonic stenosis is caused by a recurrent mutation in IGFBP7. Consistent with the recently established inhibitory role of IGFBP7 on BRAF, these patients have upregulation of the Ras/Raf/MEK/ERK pathway which may explain the overlapping cardiac phenotype with other disorders characterized by germline mutations in this pathway. The retinal phenotype appears to be mediated by a role in vascular endothelim where IGFBP7 is highly expressed. This is the first established developmental disorder in humans caused by mutation in an IGFBP.

Keywords: gene mapping • retinal detachment • mutations