Kelch-like homologue 9 mutation is associated with an early onset autosomal dominant distal myopathy.
Kelch-like homologue 9 mutation is associated with an early onset autosomal dominant distal myopathy.
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DOI：
10.1093/brain/awq108
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发表时间：
2010-07
期刊：
影响因子：
--
通讯作者：
Voit T
中科院分区：
文献类型：
--
作者：
Cirak S;von Deimling F;Sachdev S;Errington WJ;Herrmann R;Bönnemann C;Brockmann K;Hinderlich S;Lindner TH;Steinbrecher A;Hoffmann K;Privé GG;Hannink M;Nürnberg P;Voit T
远端肌病是一组异质性疾病，其特征是进行性无力和肌肉萎缩，始于远端肢体肌肉，并在后期影响近端肢体肌肉。我们研究了一个有10个患病成员的德国大家庭。胫前肌的无力和萎缩开始于8至16岁之间，随后是手部固有肌肉的萎缩。病情进展缓慢，患者直到70岁才恢复行走能力。血清肌酐激酶升高150 ~ 1400 U/l。肌肉活检显示肌病改变，而免疫组化显示肌营养不良标志物蛋白的正常表达。患者在以后的生活中，远端肢体有长袜手套分布的感觉减少。神经传导检查未发现神经病变的证据。该家族的全基因组连锁分析揭示了远端肌病的新位点9p21.2-p22.3（多点对数优势比= 4.21）。通过定位克隆，我们在Kelch-like同源基因9中发现了一个杂合突变L95F，该突变编码一个砖样Kelch蛋白。分子模拟表明，该突变可能干扰了Cullin 3与brick -a-brac结构域的相互作用。共免疫沉淀实验证实，该突变降低了kelch样同系物9-Cullin 3 - e3泛素连接酶复合物与Cullin 3的关联，该复合物参与泛素依赖性蛋白降解。我们发现了一种独特的早发常染色体显性远端肌病，它与kelch样同源9突变有关，并通过一种新的发病机制干扰正常的骨骼肌。
Distal myopathies are a heterogeneous group of disorders characterized by progressive weakness and muscular atrophy, beginning in distal limb muscles and affecting proximal limb muscles at a later stage. We studied a large German kindred with 10 affected members. Weakness and atrophy of the anterior tibial muscles started between the ages of 8 and 16 years, followed by atrophy of intrinsic hand muscles. Progression was slow, and patients retained the ability to walk until the seventh decade. Serum creatinine kinase levels were increased in the range of 150–1400 U/l. Muscle biopsies showed myopathic changes, whereas immunohistochemistry showed normal expression of marker proteins for muscular dystrophies. Patients had reduced sensation with stocking-glove distribution in the distal limbs in later life. Nerve conduction studies revealed no evidence of neuropathy. Genome-wide linkage analysis in this family revealed a new locus for distal myopathy at 9p21.2-p22.3 (multipoint logarithm of the odds ratio = 4.21). By positional cloning we found a heterozygous mutation L95F in the Kelch-like homologue 9 gene, encoding a bric-a-brac Kelch protein. Molecular modelling indicated that the mutation may interfere with the interaction of the bric-a-brac domain with Cullin 3. Coimmunoprecipitation experiments confirmed that the mutation reduces association with Cullin 3 in the Kelch-like homologue 9-Cullin 3–E3 ubiquitin ligase complex, which is involved in ubiquitin-dependent protein degradation. We identified a unique form of early onset autosomal dominant distal myopathy which is associated with a Kelch-like homologue 9 mutation and interferes with normal skeletal muscle through a novel pathogenetic mechanism.
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