title: P.Arg82Leu von Hippel-Lindau (VHL) gene mutation among three members of a family with familial bilateral pheochromocytoma in India: molecular analysis and in silico characterization.
abstract: Various missense mutations in the VHL gene have been reported among patients with familial bilateral pheochromocytoma. However, the p.Arg82Leu mutation in the VHL gene described here among patients with familial bilateral pheochromocytoma, has never been reported previously in a germline configuration. Interestingly, long-term follow-up of these patients indicated that the mutation might have had little impact on the normal function of the VHL gene, since all of them have remained asymptomatic. We further attempted to correlate this information with the results obtained by in silico analysis of this mutation using SIFT, PhD-SNP SVM profile, MutPred, PolyPhen2, and SNPs&GO prediction tools. To gain, new mechanistic insight into the structural effect, we mapped the mutation on to 3D structure (PDB ID 1LM8). Further, we analyzed the structural level changes in time scale level with respect to native and mutant protein complexes by using 12 ns molecular dynamics simulation method. Though these methods predict the mutation to have a pathogenic potential, it remains to be seen if these patients will eventually develop symptomatic disease.
authors.affiliation: Department of Endocrinology, Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: Anulekha Mary
authors.initials: AM
authors.lastname: John
authors.forename: George Priya Doss
authors.initials: GP
authors.lastname: C
authors.forename: Andrew
authors.initials: A
authors.lastname: Ebenazer
authors.forename: Mandalam Subramaniam
authors.initials: MS
authors.lastname: Seshadri
authors.forename: Aravindan
authors.initials: A
authors.lastname: Nair
authors.forename: Simon
authors.initials: S
authors.lastname: Rajaratnam
authors.forename: Rekha
authors.initials: R
authors.lastname: Pai
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence; D058070:Asymptomatic Diseases; D001483:Base Sequence; D003198:Computer Simulation; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007194:India; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human