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首页> 外文期刊>American Journal of Physiology >Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations.
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Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations.

机译：杂合，纯合和复合杂合肌球蛋白重链突变的分子和表型效应。

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摘要

Autosomal dominant familial hypertrophic cardiomyopathy (FHC) has variable penetrance and phenotype. Heterozygous mutations in MYH7 encoding beta-myosin heavy chain are the most common causes of FHC, and we proposed that "enhanced" mutant actin-myosin function is the causative molecular abnormality. We have studied individuals from families in which members have two, one, or no mutant MYH7 alleles to examine for dose effects. In one family, a member homozygous for Lys207Gln had cardiomyopathy complicated by left ventricular dilatation, systolic impairment, atrial fibrillation, and defibrillator interventions. Only one of five heterozygous relatives had FHC. Leu908Val and Asp906Gly mutations were detected in a second family in which penetrance for Leu908Val heterozygotes was 46% (21/46) and 25% (3/12) for Asp906Gly. Despite the low penetrance, hypertrophy was severe in several heterozygotes. Two individuals with both mutations developed severe FHC. The velocities of actin translocation (V(actin)) by mutant and wild-type (WT) myosins were compared in the in vitro motility assay. Compared with WT/WT, V(actin) was 34% faster for WT/D906G and 21% for WT/L908V. Surprisingly V(actin) for Leu908Val/Asp906Gly and Lys207Gln/Lys207Gln mutants were similar to WT. The apparent enhancement of mechanical performance with mutant/WT myosin was not observed for mutant/mutant myosin. This suggests that V(actin) may be a poor predictor of disease penetrance or severity and that power production may be more appropriate, or that the limited availability of double mutant patients prohibits any definitive conclusions. Finally, severe FHC in heterozygous individuals can occur despite very low penetrance, suggesting these mutations alone are insufficient to cause FHC and that uncharacterized modifying mechanisms exert powerful influences.
机译：常染色体显性家族性肥厚性心肌病（FHC）具有可变的渗透性和表型。编码β-肌球蛋白重链的MYH7中的杂合突变是FHC的最常见原因，我们提出“增强的”突变肌动蛋白-肌球蛋白功能是引起分子异常的原因。我们研究了来自成员中有两个，一个或没有突变MYH7等位基因的家庭的个体，以检查其剂量效应。在一个家庭中，Lys207Gln的纯合子成员患有心肌病，并伴有左心室扩张，收缩功能减退，心房颤动和除颤器干预。五位杂合的亲戚中只有一位患有FHC。在第二个家族中检测到Leu908Val和Asp906Gly突变，其中Leu908Val杂合子的渗透率为46％（21/46）和25％（3/12）。尽管外显率低，但在几种杂合子中肥大严重。具有两个突变的两个人发展为严重的FHC。在体外运动试验中比较了突变体和野生型（WT）肌球蛋白的肌动蛋白转运速度（V（actin））。与WT / WT相比，WT（D906G）的V（肌动蛋白）快34％，WT / L908V的V（肌动蛋白）快21％。令人惊讶地，Leu908Val / Asp906Gly和Lys207Gln / Lys207Gln突变体的V（肌动蛋白）与WT相似。对于突变体/突变型肌球蛋白，未观察到突变体/ WT肌球蛋白的机械性能明显增强。这表明V（肌动蛋白）可能不能很好地预测疾病的渗透性或严重性，并且功率产生可能更合适，或者双重突变患者的有限可获得性无法给出任何明确的结论。最后，尽管外显率很低，杂合子个体仍会发生严重的FHC，这表明仅这些突变不足以引起FHC，并且未表征的修饰机制会产生强大的影响。

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