In Silico Analysis of NovelVHLGermline Mutations in Iranian RCH Patients

Abstract

AbstractVon Hippel-Lindau (VHL) syndrome is an autosomal dominant inherited multisystem neoplasia disorder caused by theVHLtumor suppressor gene, coding for VHL protein (pVHL), variants. Various types ofVHLvariants present different clinical phenotypes that later lead to events resulting in benign or malignant lesions including Retinal Capillary Hemangioblastoma (RCH). We reported on 3 novel mutation sites observed in 3 families (5 RCH patients), including c.511A>C, c.514C>T, and c.511A>T in exon 3 of theVHLgene. According to the ACMG classifications, c.514C>T and c.511A>T variations are likely pathogenic, and c.511A>C is a variant of uncertain significance (VUS) and in accordance with autosomal dominant inheritance. The location and impact of the incidence mutations on pVHL were computed using in silico analysis. The obtained structural information and computational analysis showed that the studied mutations induce conformational changes that limit the flexibility of the pVHL interaction interface with elonginB/C, elongin C/B, and cullin2, which is necessary for HIF1 alpha binding. The recently added gene variants and their related clinical phenotypes will improve the VHL diagnosis accuracy and the patients’ population carryingVHLgene mutations. These pioneering results could be a model for future functional studies.