title: Exome sequencing reveals a novel MRE11 mutation in a patient with progressive myoclonic ataxia.
abstract: Progressive myoclonic ataxia (PMA) is a clinical syndrome defined as progressive ataxia and myoclonus and infrequent seizures in the absence of progressive dementia. Due to the extremely heterogeneous nature of PMA, a large proportion of PMA cases remain molecularly undiagnosed. The aim of this study was to clarify the molecular etiology of PMA. The patient was a 52-year-old female from consanguineous parents. She developed a jerking neck movement at age 9, which gradually expanded to her entire body. On physical examination at age 47, she exhibited generalized, spontaneous myoclonus that occurred continuously. She also presented with mild limb and truncal ataxia. An electroencephalogram revealed no abnormalities. A brain MRI displayed no atrophy of the cerebellum. Electrophysiological studies suggested myoclonus of a subcortical origin. For further evaluation, we performed exome sequencing, and we identified a novel homozygous missense mutation in the MRE11 gene (NM_005590:c.140C>T:p.A47V). Subsequently, we analyzed the expression of MRE11 and related proteins (RAD50 and NBS1) via Western blot, and they were markedly decreased compared to a healthy control. Mutations in the MRE11 gene have been known to cause an ataxia-telangiectasia-like (ATLD) disorder. Accumulating evidence has indicated that its wide phenotypic variations in ATLD correspond to genotypic differences. Interestingly, our case exhibited a relatively mild decrease in NBS1 compared to previously reported cases of a homozygous missense mutation, which may account for the milder phenotype in this patient. Moreover, together with a recently reported case of an MRE11 mutation, it is suggested that MRE11 mutations can present as PMA.
authors: Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medicine, University of Tokushima, Tokushima, Japan; Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. Electronic address: ryom@tokushima-u.ac.jp.
authors: Ryosuke
authors: R
authors: Miyamoto
authors: Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. Electronic address: morino@hiroshima-u.ac.jp.
authors: Hiroyuki
authors: H
authors: Morino
authors: Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. Electronic address: akioyoshizawa@hiroshima-u.ac.jp.
authors: Akio
authors: A
authors: Yoshizawa
authors: Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medicine, University of Tokushima, Tokushima, Japan. Electronic address: miyazaki@clin.med.tokushima-u.ac.jp.
authors: Yoshimichi
authors: Y
authors: Miyazaki
authors: Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. Electronic address: hmaru@hiroshima-u.ac.jp.
authors: Hirofumi
authors: H
authors: Maruyama
authors: Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medicine, University of Tokushima, Tokushima, Japan. Electronic address: n.murakami@clin.med.tokushima-u.ac.jp.
authors: Nagahisa
authors: N
authors: Murakami
authors: Department of Neurology, Osaka General Medical Center, Osaka, Japan. Electronic address: fukada@gh.opho.jp.
authors: Kei
authors: K
authors: Fukada
authors: Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medicine, University of Tokushima, Tokushima, Japan. Electronic address: yizumi@clin.med.tokushima-u.ac.jp.
authors: Yuishin
authors: Y
authors: Izumi
authors: Department of Genetics and Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. Electronic address: shinya@hiroshima-u.ac.jp.
authors: Shinya
authors: S
authors: Matsuura
authors: Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medicine, University of Tokushima, Tokushima, Japan. Electronic address: rkaji@clin.med.tokushima-u.ac.jp.
authors: Ryuji
authors: R
authors: Kaji
authors: Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. Electronic address: hkawakam@hiroshima-u.ac.jp.
authors: Hideshi
authors: H
authors: Kawakami
mesh_terms: D001921:Brain / Q000473:pathology; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D000076228:MRE11 Homologue Protein; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D002527:Myoclonic Cerebellar Dyssynergia / Q000235:genetics* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D000076228:MRE11 Homologue Protein
keywords: Ataxia–telangiectasia-like disorder; MRE11; Myoclonus; Neurogenetics; Progressive myoclonic ataxia; Tremor