Mutations in the N-terminal Actin-Binding Domain of Filamin C Cause a Distal Myopathy
Mutations in the N-terminal Actin-Binding Domain of Filamin C Cause a Distal Myopathy
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DOI：
10.1016/j.ajhg.2011.04.021
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发表时间：
2011-06-10
影响因子：
9.8
通讯作者：
Laing, Nigel G.
中科院分区：
文献类型：
--
作者：
Duff, Rachael M.;Tay, Valerie;Laing, Nigel G.
连锁分析的显性远端肌病，我们以前确定在一个大的澳大利亚家庭证明了一个显着的连锁区域位于7号染色体上，包括18.6 Mbp和151个基因。最强的候选基因是FLNC，因为编码的蛋白质细丝蛋白C是肌肉特异性的，并且与肌原纤维肌病相关。FLNC cDNA测序鉴定了N-末端肌动蛋白结合结构域（ABD）中的c.752T > C（p.Met251Thr）突变;该突变与疾病分离，并且在200名对照中不存在。我们鉴定了一个具有相同表型的意大利家族，并发现了与疾病分离的c.577G > A（p.Ala193Thr）细丝蛋白C ABD突变。细丝蛋白C ABD突变尚未被描述，尽管细丝蛋白A和细丝蛋白B ABD突变引起多种肌肉骨骼疾病。远端肌病的表型和肌肉病理在两个家庭不同的细丝蛋白C杆和二聚化结构域突变引起的肌原纤维肌病，因为明显参与手部肌肉和缺乏病理性蛋白质聚集。因此，与FLNA和B突变的位置一样，FLNC突变的位置决定疾病表型。两种细丝蛋白C ABD突变以类似于细丝蛋白A和细丝蛋白B ABD突变的方式增加肌动蛋白结合亲和力。c.752 T> C（p.Met251）Thr突变体细丝蛋白C ABD的细胞培养表达证明了减少的核定位，如突变体细丝蛋白A和细丝蛋白B ABD。两种细丝蛋白C ABD突变体作为全长蛋白的表达诱导细丝蛋白的聚集增加。我们的结论是细丝蛋白C ABD突变引起可识别的远端肌病，最有可能是通过增加肌动蛋白亲和力，类似于细丝蛋白A和细丝蛋白B ABD突变的病理机制。
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.