Mutations in the Mevalonate Kinase (MVK) Gene Cause Nonsyndromic Retinitis Pigmentosa

Autor: Lies H. Hoefsloot, P. Martin van Hagen, L. Ingeborgh van den Born, Carel B. Hoyng, Kornelia Neveling, Frans P.M. Cremers, Mieke Kipping-Geertsema, Anna M. Siemiatkowska, Anneke I. den Hollander, Rob W.J. Collin, Monique Stoffels, Anna Simon, Arjen Henkes
Přispěvatelé: Immunology, Ophthalmology
Rok vydání: 2013
Předmět:
Adult
Male
Proband
Oncology
medicine.medical_specialty
Pathology
Genetics and epigenetic pathways of disease [NCMLS 6]
DNA Mutational Analysis
Visual Acuity
Mevalonic Acid
Compound heterozygosity
Genomic disorders and inherited multi-system disorders [IGMD 3]
Evaluation of complex medical interventions Genomic disorders and inherited multi-system disorders [NCEBP 2]
Internal medicine
Retinitis pigmentosa
Electroretinography
medicine
Humans
Exome
Fluorescein Angiography
Exome sequencing
Mevalonate kinase deficiency
biology
business.industry
Genetic heterogeneity
Mevalonate kinase
Middle Aged
medicine.disease
Pedigree
Pathogenesis and modulation of inflammation [N4i 1]
Phosphotransferases (Alcohol Group Acceptor)
Ophthalmology
Mutation
biology.protein
Female
Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6]
business
Retinitis Pigmentosa
Tomography
Optical Coherence
Zdroj: Ophthalmology, 120, 2697-705
Ophthalmology, 120(12), 2697-2705. Elsevier Inc.
Ophthalmology, 120, 12, pp. 2697-705
ISSN: 0161-6420
Popis: Contains fulltext : 125691.pdf (Publisher’s version ) (Closed access) 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. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Databáze: OpenAIRE
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