Myofibrillar myopathy caused by a mutation in the motor domain of mouse MyHC IIb
Myofibrillar myopathy caused by a mutation in the motor domain of mouse MyHC IIb
复制标题
DOI：
10.1093/hmg/ddr605
复制
发表时间：
2012-04-15
影响因子：
3.5
通讯作者：
Blanco, Gonzalo
中科院分区：
文献类型：
--
作者：
Kurapati, Ramakrishna;McKenna, Caoimhe;Blanco, Gonzalo
Ariel是一种小鼠突变体，由于大量细胞内蛋白质聚集体的快速积累而患有骨骼肌肌原纤维变性。这种暴发性疾病是由ENU诱导的隐性突变引起的，导致骨骼肌肌球蛋白MYH4（MyHC IIb）运动域内的L342Q变化。虽然出生时正常，但纯合子小鼠从第13天开始出现后肢瘫痪，这与小鼠从发育肌球蛋白亚型转变为成年肌球蛋白亚型的时间一致。突变的肌球蛋白（MYH4（L342Q））是一种易于聚集的蛋白质。尽管该过程的速度，纯化的聚集体的生化分析表明，通常在人肌原纤维肌病中发现的蛋白质的存在下，这表明ariel聚集体的发生遵循与骨骼肌的其他构象蛋白质疾病共享的致病途径。相比之下，杂合子小鼠与对照小鼠明显且在组织学上无法区分。MYH4（L342Q）仅以野生型蛋白水平的7%存在于杂合子小鼠的肌肉中，导致分离的单纤维中的力产生的小但显著的增加，并表明杂合子中突变蛋白的消除防止了纯合子中观察到的病理变化。在人类肌肉中，小鼠MYH 4的功能等同物MYH 1中的L342Q变化的重演导致更易于聚集的蛋白质。
Ariel is a mouse mutant that suffers from skeletal muscle myofibrillar degeneration due to the rapid accumulation of large intracellular protein aggregates. This fulminant disease is caused by an ENU-induced recessive mutation resulting in an L342Q change within the motor domain of the skeletal muscle myosin protein MYH4 (MyHC IIb). Although normal at birth, homozygous mice develop hindlimb paralysis from Day 13, consistent with the timing of the switch from developmental to adult myosin isoforms in mice. The mutated myosin (MYH4(L342Q)) is an aggregate-prone protein. Notwithstanding the speed of the process, biochemical analysis of purified aggregates showed the presence of proteins typically found in human myofibrillar myopathies, suggesting that the genesis of ariel aggregates follows a pathogenic pathway shared with other conformational protein diseases of skeletal muscle. In contrast, heterozygous mice are overtly and histologically indistinguishable from control mice. MYH4(L342Q) is present in muscles from heterozygous mice at only 7% of the levels of the wild-type protein, resulting in a small but significant increase in force production in isolated single fibres and indicating that elimination of the mutant protein in heterozygotes prevents the pathological changes observed in homozygotes. Recapitulation of the L342Q change in the functional equivalent of mouse MYH4 in human muscles, MYH1, results in a more aggregate-prone protein.