TY - JOUR
T1 - Mutations in the mevalonate kinase (MVK) gene cause nonsyndromic retinitis pigmentosa
AU - Siemiatkowska, Anna M
AU - van den Born, L Ingeborgh
AU - van Hagen, P Martin
AU - Stoffels, Monique
AU - Neveling, Kornelia
AU - Henkes, Arjen
AU - Kipping-Geertsema, Mieke
AU - Hoefsloot, Lies H
AU - Hoyng, Carel B
AU - Simon, Anna
AU - den Hollander, Anneke I
AU - Cremers, Frans P M
AU - Collin, Rob W J
N1 - Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
PY - 2013/12
Y1 - 2013/12
N2 - OBJECTIVE: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous disorder characterized by night blindness and peripheral vision loss, and in many cases leads to blindness. Despite extensive knowledge about genes involved in the pathogenesis of RP, the genetic cause remains elusive in many patients. In this study, we aimed to identify novel genes that are involved in the cause of RP.DESIGN: We present a case series with mutations in the mevalonate kinase (MVK) gene.PARTICIPANTS: A total of 769 patients with nonsyndromic RP and 174 Dutch control individuals participated in this study.METHODS: Exome sequencing analysis was performed in a proband of Dutch origin who was initially diagnosed with nonsyndromic autosomal recessive RP. Mutations in MVK were identified and subsequently tested for segregation within the patient's family and screened in a large cohort of patients with genetically unsolved RP. Patients with mutations underwent extensive clinical reexamination.MAIN OUTCOME MEASURES: Digital fundus photography, spectral-domain optical coherence tomography (OCT), and fundus autofluorescence analysis were performed in patients with MVK mutations. Mevalonate kinase (MK) enzyme 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 her affected brother. Screening of our nonsyndromic RP patient cohort revealed an additional individual who was homozygous for the p.A334T alteration. Clinical reevaluation of all 3 patients showed a classic form of RP with variable extraocular symptoms, such as history of recurrent childhood febrile crises in 2 patients, mild ataxia in 1, and renal failure in 1. All 3 affected individuals showed a significantly decreased MK activity and highly elevated levels of urinary mevalonic acid.CONCLUSIONS: Although the MK activity in cells and mevalonic acid concentrations in urine are strongly aberrant and comparable to that in patients with systemic mevalonate kinase deficiency (MKD), only mild clinical symptoms related to this syndrome were observed in our patients. In the current article, we add another phenotype to the spectrum of diverging disorders associated with mutations in MVK.
AB - OBJECTIVE: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous disorder characterized by night blindness and peripheral vision loss, and in many cases leads to blindness. Despite extensive knowledge about genes involved in the pathogenesis of RP, the genetic cause remains elusive in many patients. In this study, we aimed to identify novel genes that are involved in the cause of RP.DESIGN: We present a case series with mutations in the mevalonate kinase (MVK) gene.PARTICIPANTS: A total of 769 patients with nonsyndromic RP and 174 Dutch control individuals participated in this study.METHODS: Exome sequencing analysis was performed in a proband of Dutch origin who was initially diagnosed with nonsyndromic autosomal recessive RP. Mutations in MVK were identified and subsequently tested for segregation within the patient's family and screened in a large cohort of patients with genetically unsolved RP. Patients with mutations underwent extensive clinical reexamination.MAIN OUTCOME MEASURES: Digital fundus photography, spectral-domain optical coherence tomography (OCT), and fundus autofluorescence analysis were performed in patients with MVK mutations. Mevalonate kinase (MK) enzyme 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 her affected brother. Screening of our nonsyndromic RP patient cohort revealed an additional individual who was homozygous for the p.A334T alteration. Clinical reevaluation of all 3 patients showed a classic form of RP with variable extraocular symptoms, such as history of recurrent childhood febrile crises in 2 patients, mild ataxia in 1, and renal failure in 1. All 3 affected individuals showed a significantly decreased MK activity and highly elevated levels of urinary mevalonic acid.CONCLUSIONS: Although the MK activity in cells and mevalonic acid concentrations in urine are strongly aberrant and comparable to that in patients with systemic mevalonate kinase deficiency (MKD), only mild clinical symptoms related to this syndrome were observed in our patients. In the current article, we add another phenotype to the spectrum of diverging disorders associated with mutations in MVK.
KW - Adult
KW - DNA Mutational Analysis
KW - Electroretinography
KW - Exome/genetics
KW - Female
KW - Fluorescein Angiography
KW - Humans
KW - Male
KW - Mevalonic Acid/urine
KW - Middle Aged
KW - Mutation
KW - Pedigree
KW - Phosphotransferases (Alcohol Group Acceptor)/genetics
KW - Retinitis Pigmentosa/diagnosis
KW - Tomography, Optical Coherence
KW - Visual Acuity/physiology
U2 - 10.1016/j.ophtha.2013.07.052
DO - 10.1016/j.ophtha.2013.07.052
M3 - Article
C2 - 24084495
SN - 0161-6420
VL - 120
SP - 2697
EP - 2705
JO - Ophthalmology
JF - Ophthalmology
IS - 12
ER -