Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy
Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy
复制标题
DOI：
10.1073/pnas.96.5.2305
复制
发表时间：
1999-03-02
影响因子：
11.1
通讯作者：
Wallgren-Pettersson, C
中科院分区：
文献类型：
--
作者：
Pelin, K;Hilpelä, P;Wallgren-Pettersson, C
先天性线状肌病是一种罕见的遗传性肌肉疾病，其特征是线状体的肌纤维中存在由源自 Z 盘和细丝的蛋白质组成的线状体肌纤维。在一个患有常染色体显性遗传线状肌病的澳大利亚大家族中，这种疾病是由α-原肌球蛋白基因 TPM3 突变引起的。线状肌病的典型形式是作为常染色体隐性遗传的，我们之前将其基因座分配给染色体 2q21.2-q22。我们在此表明，位于该区域的星云蛋白基因的突变与该疾病相关。星云蛋白是在横纹肌细丝中发现的一种巨大蛋白质。多种星云蛋白亚型被认为有助于 Z 盘的分子多样性。我们研究了编码 800 kDa 蛋白 Z 盘部分的 20.8 kb cDNA 的 3' 末端，并描述了来自 5 个不同种族起源家庭的患者的 6 种与疾病相关的突变。在两个近亲父母的家庭中，患者的点突变是纯合的。在一个具有非近亲结婚父母的家庭中，受影响的兄弟姐妹是两种不同突变的复合杂合子，而在另外两个各检测到一种突变的家庭中，单倍型与复合杂合性兼容。对星云蛋白 C 末端区域特异性抗体的免疫荧光研究表明，突变可能导致蛋白质截短，可能与纤维类型多样性的丧失有关，这可能与疾病发病机制有关。
The congenital nemaline myopathies are rare hereditary muscle disorders characterized by the presence in the muscle fibers of nemaline bodies consisting of proteins derived from the Z disc and thin filament. In a single large Australian family with an autosomal dominant form of nemaline myopathy, the disease is caused by a mutation in the a-tropomyosin gene TPM3. The typical form of nemaline myopathy is inherited as an autosomal recessive trait, the locus of which we previously assigned to chromosome 2q21.2-q22. We show here that mutations in the nebulin gene located within this region are associated with the disease. The nebulin protein is a giant protein found in the thin filaments of striated muscle. A variety of nebulin isoforms are thought to contribute to the molecular diversity of Z discs. We have studied the 3' end of the 20.8-kb cDNA encoding the Z disc part of the 800-kDa protein and describe six disease-associated mutations in patients from five families of different ethnic origins. In two families with consanguineous parents, the patients were homozygous for point mutations. In one family with nonconsanguineous parents, the affected siblings were compound heterozygotes for two different mutations, and in two further families with one detected mutation each, haplotypes are compatible with compound heterozygosity. Immunofluorescence studies with antibodies specific to the C-terminal region of nebulin indicate that the mutations may cause protein truncation possibly associated with loss of fiber-type diversity, which may be relevant to disease pathogenesis.