Reference - Detail
| RRC ID | 60897 |
|---|---|
| Author | 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. |
| Title | Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy. |
| Journal | 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. |
| Volume | 88(6) |
| Pages | 729-740 |
| Published | 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 |
| Times Cited | 72 |
| Altmetric score |
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 5 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| DNA material | NRCD human cDNA clones (RDB06607) ARi57A02 (HKR182802) |