Identification of a novel mutation in the mevalonate kinase gene associated with retinitis pigmentosa

Abstract

Purpose: To identify the mutation leading to recessive retinitis pigmentosa (RP) in a family that was found to be negative for DNA changes following hybridization chip analysis.

Methods: The family analyzed included a kindred of three (two affected, one unaffected), born from healthy and unrelated parents. Genetic analyses were performed by whole exome sequencing (WES) in all five members of the family. Data processing, which included read alignment, variant calling and variant filtering, was performed using an in silico pipeline that was developed in-house. All variants that survived our filtering procedures and represented candidate mutations were verified by Sanger sequencing in the index patient and subsequently tested for segregation within the disease in the other members of the family.

Results: We identified two compound heterozygous mutations (p.A334T and p.G337R) in the mevalonate kinase gene (MVK) in the two affected siblings. Segregation analysis was compatible with a recessive mode of inheritance. MVK was recently found to be associated with recessive, nonsyndromic RP. While p.A334T was previously reported to be a pathogenic variant, p.G337R likely represents a novel mutation. Glycine at codon 337 is invariant in all MVK orthologues that we could analyze, from yeast to human, and lies within a stretch of amino acid residues that is rather conserved though evolution. Furthermore, p.G337R was absent from the genome of 90 control individuals, strengthening the idea that it is a bona fide mutation.

Conclusions: To date, only 3 mutations associated with retinal degeneration have been discovered in MVK. Following the use of WES and a specific analytical pipeline that aims at identifying rare and pathogenic variants, we have detected a new putative mutation associated with recessive RP in a non-consanguineous family. Functional studies on p.G337R are currently ongoing to ascertain the potential pathogenic role of p.G337R on the MVK protein.