Novel VHL Germline Mutations in Iranian RCH Patients
Kowsar Bagherzadeh1 , Fatemeh Azimi1 , Golnaz Khakpoor1 , Reza Mirshahi1 , Ahad Sedaghat1 , Masood Naseripour1 *
- Eye Research Center, the Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
Abstract: VonVon Hippel-Lindau (VHL) syndrome is an autosomal dominant inherited multisystem neoplasia disorder caused by VHL tumor suppressor gene variants, coding for VHL protein (pVHL). 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).
Methods: Three families (5 RCH patients) with novel mutations are included in this study. VHL mutational analysis was performed employing Sanger sequencing technique. Molecular dynamic (MDs) simulations studies were carried out for analyzing conformational changes occurred as a result of the mutations in VHL protein structure and compared with that of the native structure.
Results: Novel mutation sites, including c.511A>C, c.511A>T and c.514C>T in exon 3 of the VHL gene were identified. According to the ACMG classifications, c.514C>T and c.511A>C are variations of uncertain significance (VUS) and c.511A>T is a likely pathogenic variant. The location and impact of the incidence mutations on pVHL were computed using in silico analysis. The overall fluctuations of the protein structure show a significantly lower degree of flexibility in the ?-domain in the mutant structures compared to that of the native form.
Conclusion: 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 cullin2, which is necessary for HIF1 alpha binding. The recently added gene variants and their related clinical phenotypes will improve VHL diagnosis accuracy and the patients’ population carrying VHL gene mutations. These pioneering results can be considered as a model for future functional studies.
