MFN2transcripts escaping from nonsense-mediated mRNA decay pathway cause Charcot-Marie-Tooth disease type 2A2
| Autor: | Chimeglkham Banzrai, Antonio Orlacchio, Ryosuke Miyamoto, Lucia Pedace, Ryuji Kaji, Atsuko Mori, Ryosuke Oki, Hiroyuki Nodera, Yoshihiko Nishida, Toshitaka Kawarai, Hiroshi Takashima, Naoko Takamatsu, Akihiro Hashiguchi, Yusuke Osaki, Yuishin Izumi, Kanto Yamasaki, Yujiro Higuchi |
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| Rok vydání: | 2016 |
| Předmět: |
Male
Neurogenetics Surgery Arts and Humanities (miscellaneous) Neurology (clinical) Psychiatry and Mental Health 0301 basic medicine Nonsense-mediated decay Population Disease Biology Bioinformatics GTP Phosphohydrolases Mitochondrial Proteins 03 medical and health sciences symbols.namesake 0302 clinical medicine Atrophy Japan Charcot-Marie-Tooth Disease medicine Humans Missense mutation education Sanger sequencing Genetics education.field_of_study medicine.disease Nonsense Mediated mRNA Decay Psychiatry and Mental health 030104 developmental biology Mutation symbols Female Restriction fragment length polymorphism 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neurology, Neurosurgery & Psychiatry. 87:1263-1265 |
| ISSN: | 1468-330X 0022-3050 |
| Popis: | Charcot-Marie-Tooth disease (CMT) is a hereditary peripheral neuropathy characterised by length-dependent degeneration of the motor and sensory nerve fibres with consequent distal muscle weakness, atrophy and mild sensory loss, primarily in lower limbs. The historic prevalence of CMT in the general population is 1 in 2500 individuals,1 while the present prevalence is 1 in 1214 individuals.2 Missense mutations in the mitofusion 2 gene ( MFN2 ; OMIM*608506) have been found in most axonal forms (CMT type 2; CMT2) with autosomal dominant inheritance, and truncation mutations can be found in a few cases with seemingly autosomal recessive inheritance or sporadic cases. A dominant negative or toxic gain-of-function mechanism has been postulated in the autosomal dominant mode; however, the biological effect(s) by mutant MFN2 may vary depending on the nature of the mutations.3 This report describes a unique pathomechanism identified in a large Japanese MFN2 -CMT2A2 family. The currently living family members were examined by movement disorder specialists (TK, RM, HN, YN and YI). Neurological assessments, including the Charcot-Marie-Tooth disease neuropathy score V.2, electrophysiology of peripheral nerves and neuroimaging analyses, were carried out. Genetic analyses were conducted as described in online supplementary data, including targeted resequencing, Sanger sequencing, restriction fragment length polymorphism (RFLP) analysis and semiquantitative reverse-transcription (RT)-PCR. Peripheral T-cells were cultured with a nonsense-mediated decay (NMD) inhibitor, emetine, in order to evaluate the effect by NMD system. A bioinformatic analysis and literature review were also carried out. The details are described in online supplementary data. ### Supplementary data [jnnp-2015-312646supp.pdf] The family is composed of a three-generation kindred, with autosomal dominant inheritance (figure 1A). Nine individuals were diagnosed as ‘certainly affected’ and classified as having Charcot-Marie-Tooth disease. Clinical and laboratory features of all affected individuals are summarised in online supplementary tables S1 and S2, and figure S1. Age-at-onset was 5 or … |
| Databáze: | OpenAIRE |
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