論文 - 詳細
| RRC ID | 60897 |
|---|---|
| 著者 | Duff RM, Tay V, Hackman P, Ravenscroft G, McLean C, Kennedy P, Steinbach A, Schöffler W, van der Ven PFM, Fürst DO, Song J, Djinović-Carugo K, Penttilä S, Raheem O, Reardon K, Malandrini A, Gambelli S, Villanova M, Nowak KJ, Williams DR, Landers JE, Brown RH Jr, Udd B, Laing NG. |
| タイトル | Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy. |
| ジャーナル | Am J Hum Genet |
| Abstract |
Linkage analysis of the dominant distal myopathy we previously identified in a large Australian family demonstrated one significant linkage region located on chromosome 7 and encompassing 18.6 Mbp and 151 genes. The strongest candidate gene was FLNC because filamin C, the encoded protein, is muscle-specific and associated with myofibrillar myopathy. Sequencing of FLNC cDNA identified a c.752T>C (p.Met251Thr) mutation in the N-terminal actin-binding domain (ABD); this mutation segregated with the disease and was absent in 200 controls. We identified an Italian family with the same phenotype and found a c.577G>A (p.Ala193Thr) filamin C ABD mutation that segregated with the disease. Filamin C ABD mutations have not been described, although filamin A and filamin B ABD mutations cause multiple musculoskeletal disorders. The distal myopathy phenotype and muscle pathology in the two families differ from myofibrillar myopathies caused by filamin C rod and dimerization domain mutations because of the distinct involvement of hand muscles and lack of pathological protein aggregation. Thus, like the position of FLNA and B mutations, the position of the FLNC mutation determines disease phenotype. The two filamin C ABD mutations increase actin-binding affinity in a manner similar to filamin A and filamin B ABD mutations. Cell-culture expression of the c.752T>C (p.Met251)Thr mutant filamin C ABD demonstrated reduced nuclear localization as did mutant filamin A and filamin B ABDs. Expression of both filamin C ABD mutants as full-length proteins induced increased aggregation of filamin. We conclude filamin C ABD mutations cause a recognizable distal myopathy, most likely through increased actin affinity, similar to the pathological mechanism of filamin A and filamin B ABD mutations. |
| 巻・号 | 88(6) |
| ページ | 729-740 |
| 公開日 | 2011-6-10 |
| DOI | 10.1016/j.ajhg.2011.04.021 |
| PII | S0002-9297(11)00162-5 |
| PMID | 21620354 |
| PMC | PMC3113346 |
| MeSH | Actins / metabolism Adult Aged Australia Chromosomes, Human, Pair 7 / genetics Contractile Proteins / genetics* Contractile Proteins / metabolism Distal Myopathies / genetics* Distal Myopathies / metabolism Distal Myopathies / pathology Female Filamins Humans Italy Male Microfilament Proteins / genetics* Microfilament Proteins / metabolism Middle Aged Mutation Pedigree Protein Structure, Tertiary / genetics |
| IF | 10.502 |
| 引用数 | 72 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 5 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | NRCD human cDNA clones (RDB06607) ARi57A02 (HKR182802) |