Myosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1
Myosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1
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DOI：
10.1093/hmg/ddp587
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发表时间：
2010-04-01
影响因子：
3.5
通讯作者：
Dobbs, Mathew B.
中科院分区：
文献类型：
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作者：
Gurnett, Christina A.;Desruisseau, David M.;Dobbs, Mathew B.
远端关节挛缩I型（DA1）是一种以先天性手和脚挛缩为特征的疾病，很少有基因被确定。在这里，我们描述了一个五代家族与DA1分离作为一个常染色体显性疾病与完全外显率。利用Affymetrix GeneChip Mapping 10K数据对该家族12个受影响成员进行全基因组连锁分析，发现12q染色体上的多点LODmax为3.27。对位于连锁区间内的慢抽搐骨骼肌肌球蛋白结合蛋白C1 （MYBPC1）进行测序，发现该家族中存在与疾病分离的错义突变（C . 706t > C），并导致W236R氨基酸替代。在另一个DA1家族中发现了第二个MYBPC1错义突变（C . 2566t > C）（Y856H），占MYBPC1突变频率的13%（15分之2）。受影响患者的骨骼肌活检显示I型（慢抽搐）纤维比II型纤维小。含有WT和DA1突变的绿色荧光蛋白（GFP）标记的MYBPC1构建体在小鼠骨骼肌中的表达显示出强大的肌肉组织定位。相反，当含有相应的MYBPC3氨基酸取代（R326Q, E334K）的非融合GFP和MYBPC1蛋白表达引起肥厚性心肌病时，可以看到更弥漫性的定位。这些发现表明MYBPC1是一个负责DA1的新基因，尽管疾病的机制可能与一些心肌MYBPC3突变导致肥厚性心肌病的机制不同。
Distal arthrogryposis type I (DA1) is a disorder characterized by congenital contractures of the hands and feet for which few genes have been identified. Here we describe a five-generation family with DA1 segregating as an autosomal dominant disorder with complete penetrance. Genome-wide linkage analysis using Affymetrix GeneChip Mapping 10K data from 12 affected members of this family revealed a multipoint LODmax of 3.27 on chromosome 12q. Sequencing of the slow-twitch skeletal muscle myosin binding protein C1 (MYBPC1), located within the linkage interval, revealed a missense mutation (c.706T > C) that segregated with disease in this family and causes a W236R amino acid substitution. A second MYBPC1 missense mutation was identified (c.2566T > C)(Y856H) in another family with DA1, accounting for an MYBPC1 mutation frequency of 13% (two of 15). Skeletal muscle biopsies from affected patients showed type I (slow-twitch) fibers were smaller than type II fibers. Expression of a green fluorescent protein (GFP)-tagged MYBPC1 construct containing WT and DA1 mutations in mouse skeletal muscle revealed robust sarcomeric localization. In contrast, a more diffuse localization was seen when non-fused GFP and MYBPC1 proteins containing corresponding MYBPC3 amino acid substitutions (R326Q, E334K) that cause hypertrophic cardiomyopathy were expressed. These findings reveal that the MYBPC1 is a novel gene responsible for DA1, though the mechanism of disease may differ from how some cardiac MYBPC3 mutations cause hypertrophic cardiomyopathy.