Dysferlin mutations in Japanese Miyoshi myopathy

Takahashi, Toshiaki; Akiyama, Masashi; Tateyama, Masao; Kondo, Eri; Mizuno, Tomohito; Onodera, Yoshiaki; Takano, Ryosuke; Kawai, Hisaomi; Kamakura, Keiko; Mochizuki, Hitoshi; Shizuka-Ikeda, Masami; Nakagawa, Masanori; Yoshida, Yasuhiko; Akanuma, Jun; Hoshino, Koyu; Saito, Hiroshi; Nishizawa, Masatoyo; Kato, Shigeo; Saito, Kayoko; Miyachi, Takafumi; Yamashita, Hiroshi; Kawai, Mitsuru; Matsumura, Tatsuro; Kuzuhara, Shigeki; Ibi, Tohru; Sahashi, K.; Nakai, Hiroyuki; Kohnosu, T.; Nonaka, Ikuya; Arahata, Kiichi; Brown, Robert H.; Itoyama, Yasuto

doi:10.1212/01.wnl.0000068333.43005.12

Cited by 73 publications

(80 citation statements)

References 23 publications

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“…All mutations in the DYSF gene found to date are point mutations or small deletions or insertions distributed all over the entire coding sequence. No hotspot has been identified, and missense as well as nonsense or frameshift mutations have been reported (Aoki et al, 2001;Takahashi et al, 2003). Consequently, mutation analysis of DYSF remains a time-consuming challenging task accounting for the paucity of large series.…”

Section: Doi: 101002/humu9355mentioning

confidence: 99%

Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies

et al. 2005

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DYSF encoding dysferlin is mutated in Miyoshi myopathy and Limb-Girdle Muscular Dystrophy type 2B, the two main phenotypes recognized in dysferlinopathies. Dysferlin deficiency in muscle is the most relevant feature for the diagnosis of dysferlinopathy and prompts the search for mutations in DYSF. DYSF, located on chromosome 2p13, contains 55 coding exons and spans 150 kb of genomic DNA. We performed a genomic analysis of the DYSF coding sequence in 34 unrelated patients from various ethnic origins. All patients showed an absence or drastic decrease of dysferlin expression in muscle. A primary screening of DYSF using SSCP or dHPLC of PCR products of each of 55 exons of the gene was followed by sequencing whenever a sequence variation was detected. All together, 54 sequence variations were identified in DYSF, 50 of which predicting either a truncated protein or one amino-acid substitution and most of them (34 out of 54) being novel. In 23 patients, we identified two pathogenic mutations, while only one was identified in 11 patients. These mutations were widely spread in the coding sequence of the gene without any mutational "hotspot."

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Section: Doi: 101002/humu9355mentioning

confidence: 99%

Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies

et al. 2005

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“…Mutational data from large cohorts of patients repeatedly revealed a large mutational spectrum for the DYSF gene, with a high proportion of missense changes, or frameshifting insertions and/or deletions (for example, (Aoki, et al, 2001;Cagliani, et al, 2003;De Luna, et al, 2007;Guglieri, et al, 2008;Klinge, et al, 2010;Krahn, et al, 2009a;Mahjneh, et al, 1996;Nguyen, et al, 2005;Tagawa, et al, 2003;Takahashi, et al, 2003)). Accordingly, most of the UMD-DYSF entries correspond to "private" or rare DYSF disease-causing mutations.…”

Section: General Statisticsmentioning

confidence: 99%

UMD-DYSF, a novel locus specific database for the compilation and interactive analysis of mutations in the dysferlin gene

et al. 2011

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Mutations in the dysferlin gene (DYSF) lead to a complete or partial absence of the dysferlin protein in skeletal muscles and are at the origin of dysferlinopathies, a heterogeneous group of rare autosomal recessive inherited neuromuscular disorders. As a step towards a better understanding of the DYSF mutational spectrum, and towards possible inclusion of patients in future therapeutic clinical trials, we set up the Universal Mutation Database for Dysferlin (UMD-DYSF), a Locus-Specific Database developed with the UMD® software. The main objective of UMD-DYSF is to provide an updated compilation of mutational data and relevant interactive tools for the analysis of DYSF sequence variants, for diagnostic and research purposes. In particular, specific algorithms can facilitate the interpretation of newly identified intronic, missense-or isosemantic-exonic sequence variants, a problem encountered recurrently during genetic diagnosis in dysferlinopathies. UMD-DYSF v1.0 is freely accessible at www.umd.be/DYSF/. It contains a total of 742 mutational entries corresponding to 266 different disease-causing mutations identified in 558 patients worldwide diagnosed with dysferlinopathy. This article presents for the first time a comprehensive analysis of the dysferlin mutational spectrum based on all compiled DYSF diseasecausing mutations reported in the literature to date, and using the main bioinformatics tools offered in UMD-DYSF.

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“…Therefore, an easier method to screen for common mutations is now required to facilitate DNA-based diagnosis of dysferlinopathy. We previously showed that 4 mutations, c.937+1G>A, c.1566C>G, c.2997G>T and c.3373delG account for 50% of all the mutations identified in Japanese dysferlinopathy patients (4). In this study, we have developed a simple and rapid screening method to detect these mutational hot spots in the dysferlin gene using fluorescent primer extension.…”

Section: Introductionmentioning

confidence: 99%

Rapid Screening for Japanese Dysferlinopathy by Fluorescent Primer Extension

et al. 2010

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Objective Mutations in the dysferlin gene cause limb-girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy (MM), which are collectively named dysferlinopathy. Dysferlinopathy is the most frequent type of LGMD in the Japanese population. Molecular genetic analysis is essential for the diagnosis of dysferlinopathy because of its variable immunohistochemical patterns of biopsied muscles, including patterns similar to normal controls. The analysis of the entire dysferlin gene however, is time-consuming and laborious; therefore a simple and rapid screening method to detect hot spot mutations in the dysferlin gene is essential for the diagnosis of dysferlinopathy. Methods We previously showed that 4 mutations, c.937+1G>A, c.1566C>G, c.2997G>T and c.3373delG account for 50% of all the mutations identified in Japanese dysferlinopathy patients. We performed a onetube multiplex PCR, followed by extension of primers for each mutation with a fluorescence-labeled dideoxynucleotide to screen the 4 hot spot mutations. Results The multiplex primer-extension reaction was developed on samples of known mutations. The extension products were represented as 4 different peaks that corresponded to a mutated nucleotide on electropherogram. Using the developed screening method, we were able to detect mutations in these hot spots in 3 samples out of 8 clinically suspected LGMD2B/MM patients in only approximately 8 hours. These 3 cases were definitely diagnosed as LGMD2B/MM by exonic sequencing. Conclusion We have developed a simple and rapid screening method which could facilitate the definitive diagnosis of dysferlinopathy, contributing to an understanding of the genotype-phenotype correlations for dysferlinopathy.

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Dysferlin mutations in Japanese Miyoshi myopathy

Cited by 73 publications

References 23 publications

Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies

Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies

UMD-DYSF, a novel locus specific database for the compilation and interactive analysis of mutations in the dysferlin gene

Rapid Screening for Japanese Dysferlinopathy by Fluorescent Primer Extension

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