Molecular consequences of dominant Bethlem myopathy collagen VI mutations
Molecular consequences of dominant Bethlem myopathy collagen VI mutations
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DOI：
10.1002/ana.21213
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发表时间：
2007-10-01
影响因子：
11.2
通讯作者：
Lamande, Shireen R.
中科院分区：
文献类型：
--
作者：
Baker, Naomi L.;Morgelin, Matthias;Lamande, Shireen R.
目的：三种胶原VI基因的显性突变导致Bethlem肌病，这是一种以近端肌肉无力和手指、手腕和脚踝的常见挛缩为特征的疾病。尽管在Bethlem肌病患者中已经鉴定出20多种不同的显性突变，但是仅研究了其中一部分的生物合成结果，并且在许多情况下，致病机制仍然未知。方法：我们筛选了14名Bethlem肌病患者的VI型胶原突变，并对VI型胶原生物合成和细胞内和细胞外组装进行了详细分析。在8例患者中发现VI型胶原异常。一名患者产生了大约一半的正常量的α 1（VI）信使RNA和减少量的胶原VI蛋白。两名患者先前报告的突变导致COL 6A 1外显子14跳读，三名患者有新的突变导致三螺旋结构域N末端的框内缺失。这些突变对胶原VI细胞内和细胞外组装具有不同且复杂的影响。两名患者在C 0 L 6A 2和C 0 L 6A 3的A结构域中具有单个氨基酸取代。VI型胶原细胞内和细胞外组装是正常的，在这些patients.Interpretation：解剖VI型胶原突变的致病机制的关键在于在VI型胶原的生物合成和组装的详细分析。大多数突变导致结构异常的胶原VI的分泌和沉积。然而，一个A-结构域突变对组装没有可检测的影响，表明它通过损害肌肉细胞外基质中的胶原VI相互作用来起作用。
Objective: Dominant mutations in the three collagen VI genes cause Bethlem myopathy, a disorder characterized by proximal muscle weakness and commonly contractures of the fingers, wrists, and ankles. Although more than 20 different dominant mutations have been identified in Bethlem myopathy patients, the biosynthetic consequences of only a subset of these have been studied, and in many cases, the pathogenic mechanisms remain unknown.Methods: We have screened fourteen Bethlem myopathy patients for collagen VI mutations and performed detailed analyses of collagen VI biosynthesis and intracellular and extracellular assembly.Results: Collagen VI abnormalities were identified in eight patients. One patient produced around half the normal amount of alpha 1(VI) messenger RNA and reduced amounts of collagen VI protein. Two patients had a previously reported mutation causing skipping of COL6A1 exon 14, and three patients had novel mutations leading to in-frame deletions toward the N-terminal end of the triple-helical domain. These mutations have different and complex effects on collagen VI intracellular and extracellular assembly. Two patients had single amino acid substitutions in the A-domains of COL6A2 and COL6A3. Collagen VI intracellular and extracellular assembly was normal in one of these patients.Interpretation: The key to dissecting the pathogenic mechanisms of collagen VI mutations lies in detailed analysis of collagen VI biosynthesis and assembly. The majority of mutations result in secretion and deposition of structurally abnormal collagen VI. However, one A-domain mutation had no detectable effect on assembly, suggesting that it acts by compromising collagen VI interactions in the extracellular matrix of muscle.