Autosomal dominant myopathy:: Missense mutation (Glu-706 → Lys) in the myosin heavy chain IIa gene
Autosomal dominant myopathy:: Missense mutation (Glu-706 → Lys) in the myosin heavy chain IIa gene
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DOI：
10.1073/pnas.250289597
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发表时间：
2000-12-19
影响因子：
11.1
通讯作者：
Wahlström, J
中科院分区：
文献类型：
--
作者：
Martinsson, T;Oldfors, A;Wahlström, J
我们在此报告与快速肌球蛋白重链（MyHC）基因突变相关的人类肌病，以及遗传性包涵体肌病的遗传缺陷。这种疾病以前曾在一个“常染色体显性肌病，伴有关节挛缩、眼麻痹和边缘空泡”的家族中被描述过。连锁分析和辐射杂交定位表明，该基因位点（Human Genome Map locus name: IBM3）位于染色体17p13的2mb区域，该区域也有MyHC基因簇。这些基因包括编码胚胎、IIa、IIx/d、IIb、围产期和眼外myhc的基因。该家族患者的肌肉活检形态学分析表明，2A型纤维经常出现异常，而其他类型的纤维则表现正常。这一观察结果促使我们研究MyHC-IIa基因，因为MyHC-IIa是ZA型纤维的主要亚型。该基因的完整基因组序列是通过使用“计算机”策略推断出来的。该基因由38个外显子组成，在患者和对照组中进行了完全突变扫描。我们发现了一个错义突变，Glu-706 -> Lys，它位于运动结构域的一个高度保守的区域，即所谓的SH1螺旋区域。通过构象变化，该区域将核苷酸结合位点的活性传递给颈部区域，导致杠杆臂摆动。该区域的突变可能导致肌凝蛋白功能失调，与家族中的疾病相一致。
We here report on a human myopathy associated with a mutation in a fast myosin heavy chain (MyHC) gene, and also the genetic defect in a hereditary inclusion body myopathy. The disorder has previously been described in a family with an "autosomal dominant myopathy, with joint contractures, ophthalmoplegia, and rimmed vacuoles." Linkage analysis and radiation hybrid mapping showed that the gene locus (Human Genome Map locus name: IBM3) is situated in a 2-Mb region of chromosome 17p13, where also a cluster of MyHC genes is located. These include the genes encoding embryonic, IIa, IIx/d, IIb, perinatal, and extraocular MyHCs. Morphological analysis of muscle biopsies from patients from the family indicated to us that the type 2A fibers frequently were abnormal, whereas other fiber types appeared normal. This observation prompted us to investigate the MyHC-IIa gene, since MyHC-IIa is the major isoform in type ZA fibers. The complete genomic sequence for this gene was deduced by using an "in silico" strategy. The gene, found to consist of 38 exons, was subjected to a complete mutation scan in patients and controls. We identified a missense mutation, Glu-706 --> Lys, which is located in a highly conserved region of the motor domain, the so-called SH1 helix region. By conformational changes this region communicates activity at the nucleotide-binding site to the neck region, resulting in the lever arm swing. The mutation in this region is likely to result in a dysfunctional myosin, compatible with the disorder in the family.