Anna M Siemiatkowska1, L Ingeborgh van den Born2, P Martin van Hagen3, Monique Stoffels4, Kornelia Neveling5, Arjen Henkes1, Mieke Kipping-Geertsema1, Lies H Hoefsloot1, Carel B Hoyng6, Anna Simon4, Anneke I den Hollander7, Frans P M Cremers8, Rob W J Collin9. 1. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands. 2. The Rotterdam Eye Hospital, Rotterdam, The Netherlands. 3. Department of Immunology, Erasmus University Medical Centre, Rotterdam, The Netherlands. 4. Department of General Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands; Nijmegen Centre for Infection, Inflammation and Immunity (N4i), Radboud University Medical Centre, Nijmegen, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands. 5. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands. 6. Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, The Netherlands. 7. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands; Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands; Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, The Netherlands. 8. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands. 9. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands; Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands. Electronic address: r.collin@gen.umcn.nl.
Abstract
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.
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.
Authors: Anna M Siemiatkowska; Rob W J Collin; Anneke I den Hollander; Frans P M Cremers Journal: Cold Spring Harb Perspect Med Date: 2014-06-17 Impact factor: 6.915
Authors: Kinga M Bujakowska; Qi Zhang; Anna M Siemiatkowska; Qin Liu; Emily Place; Marni J Falk; Mark Consugar; Marie-Elise Lancelot; Aline Antonio; Christine Lonjou; Wassila Carpentier; Saddek Mohand-Saïd; Anneke I den Hollander; Frans P M Cremers; Bart P Leroy; Xiaowu Gai; José-Alain Sahel; L Ingeborgh van den Born; Rob W J Collin; Christina Zeitz; Isabelle Audo; Eric A Pierce Journal: Hum Mol Genet Date: 2014-08-28 Impact factor: 6.150
Authors: Yajing Angela Xie; Winston Lee; Carolyn Cai; Tomasz Gambin; Kalev Nõupuu; Tharikarn Sujirakul; Carmen Ayuso; Shalini Jhangiani; Donna Muzny; Eric Boerwinkle; Richard Gibbs; Vivienne C Greenstein; James R Lupski; Stephen H Tsang; Rando Allikmets Journal: Hum Mol Genet Date: 2014-06-10 Impact factor: 6.150