Mutations in MVK cause non-syndromic autosomal recessive retinitis pigmentosa

Abstract

Purpose: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous retinal disease. Typically beginning with night blindness, RP is characterized by visual field loss followed by deterioration of visual acuity, which may ultimately lead to complete blindness. Despite extensive knowledge about genes involved in RP pathogenesis, the genetic cause remains elusive in many patients. In this study, we aimed to identify novel genes that are involved in the etiology of RP.

Methods: Exome sequence analysis was performed in a proband of Dutch origin that was first diagnosed with non-syndromic autosomal recessive RP. Identified mutations in the mevalonate kinase (MVK) gene were subsequently tested for segregation within the family and in a large cohort of genetically unsolved RP patients. Patients with mutations underwent extensive clinical re-examination. Mevalonate kinase enzyme (MK) activity was analyzed in cultured lymphoblastoid cells and mevalonic acid levels were measured in urine samples.

Results: Exome variant filtering and prioritization led to the identification of compound heterozygous mutations in MVK (p.I268T and p.A334T) in the proband and his affected sibling. Recessive mutations in MVK are known to cause mevalonic kinase deficiencies (MKD): mevalonic aciduria (MVA), sometimes accompanied by RP, and hyper-IgD and periodic fever syndrome (HIDS). Screening of 269 non-syndromic RP patients revealed an individual who was homozygous for the p.A334T alteration. None of these patients displayed any of the other classical extra-ocular symptoms that are usually associated with recessive mutations in MVK, namely elevated IgD levels, recurrent febrile crises psychomotor retardation, progressive cerebellar ataxia or dysmorphic features. In all three affected individuals, mevalonate kinase activity was significantly decreased and mevalonic acid levels in urine were elevated.

Conclusions: Although the MK activity in cells and mevalonic acid concentrations in urine are abnormal and within the range of patients with mevalonate kinase deficiency, no apparent other clinical symptoms associated with classical MKD were observed in our patients. This study adds MVK to the group of genes that appear to be associated with non-syndromic retinitis pigmentosa.

Keywords: 696 retinal degenerations: hereditary • 539 genetics • 537 gene screening