title: Molecular Characterization of a Novel Germline VHL Mutation by Extensive In Silico Analysis in an Indian Family with Von Hippel-Lindau Disease.
abstract: Von Hippel-Lindau [VHL] disease, an autosomal dominant hereditary cancer syndrome, is well known for its complex genotype-phenotype correlations. We looked for germline mutations in the VHL gene in an affected multiplex family with Type 1 VHL disease. Real-Time quantitative PCR for deletions and Sanger sequencing of coding regions along with flanking intronic regions were performed in two affected individuals and one related individual. Direct sequencing identified a novel heterozygous single nucleotide base substitution in both the affected members tested, segregating with VHL phenotype in this family. This variant in exon 3, c.473T>A, results in substitution of leucine, a highly conserved acid, to glutamine at position 158 [p.L158Q] and has not been reported thus far as a variant associated with disease causation. Further, this variant was not observed in 50 age and ethnicity matched healthy individuals. Extensive in silico prediction analysis along with molecular dynamics simulation revealed significant deleterious nature of the substitution L158Q on pVHL. The results of this study when collated support the view that the missense variation p.L158Q in the Elongin C binding domain of pVHL may be disease causing.
authors.affiliation: Department of Clinical Genetics, Christian Medical College, Vellore, Tamil Nadu 632004, India.
authors.forename: Gautham
authors.initials: G
authors.lastname: Arunachal
authors.affiliation: Department of Clinical Genetics, Christian Medical College, Vellore, Tamil Nadu 632004, India.
authors.forename: Divya
authors.initials: D
authors.lastname: Pachat
authors.affiliation: School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu 632014, India.
authors.forename: C George Priya
authors.initials: CG
authors.lastname: Doss
authors.affiliation: Department of Clinical Genetics, Christian Medical College, Vellore, Tamil Nadu 632004, India.
authors.forename: Sumita
authors.initials: S
authors.lastname: Danda
authors.affiliation: Department of Pathology, Christian Medical College, Vellore, Tamil Nadu 632004, India.
authors.forename: Rekha
authors.initials: R
authors.lastname: Pai
authors.affiliation: Department of Pathology, Christian Medical College, Vellore, Tamil Nadu 632004, India.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ebenazer