In Silico Analysis of Novel VHL Germline Mutations in Iranian RCH Patients

Von Hippel-Lindau (VHL) syndrome is an autosomal dominant inherited multisystem neoplasia disorder caused by VHL tumor suppressor gene, coding for VHL protein (pVHL), variants. Various types of VHL variants present different clinical phenotypes that later lead to events resulting in benign or malignant lesions including Retinal Capillary Hemangioblastoma (RCH). Here in, ۳ novel mutation sites observed in ۳ families (۵ RCH patients), including c.۵۱۱A>C, c.۵۱۴C>T, and c.۵۱۱A>T in exon ۳ of the VHL gene are reported for the first time. According to ACMG classifications, c.۵۱۴C>T and c.۵۱۱A>T variations are likely pathogenic, and c.۵۱۱A>C is a variant of uncertain significance (VUS) 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 pVHL interaction interface with elonginB/C, elongin C/B, and cullin۲, which is necessary for hypoxia-inducible factor ۱-alpha binding. The recently added gene variants and their related clinical phenotypes will improve the VHL diagnosis accuracy and the patients’ population carrying VHL gene mutations. These pioneering results can be used as a model for future functional studies

کلیدواژه ها:

Von Hippel-Lindau (VHL) ، Retinal Capillary Hemangioblastoma (RCH) ، Molecular Dynamic Simulations ، Novel Mutations