Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology
Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology
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DOI：
10.1161/01.cir.0000018444.47798.94
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发表时间：
2002-05-21
期刊：
影响因子：
37.8
通讯作者：
Driscoll, DJ
中科院分区：
文献类型：
--
作者：
Olson, TM;Karst, ML;Driscoll, DJ
背景-常染色体显性肥厚型心肌病（HCM）是由safcomeric蛋白的遗传缺陷引起的。我们测试的假设，hornooziness的一个肌节蛋白缺陷可能会导致隐性HCM.Methods和结果，我们研究了一个家庭与早发性心肌病在3个兄弟姐妹，特点是中腔肥大和限制性生理。跨越8个常染色体显性遗传HCM基因的DNA标记的基因分型揭示了受影响的儿童在肌球蛋白基因座的必需轻链处具有相同的父源和母源单倍型。测序结果表明，这些人是纯合子的Glu 143 Lys取代的高度保守的氨基酸，是在150个控制。有一个Glu 143 Lys等位基因的家庭成员即使在成年后期也有正常的超声心动图和心电图，而有两个突变等位基因的家庭成员在儿童时期患上了严重的心肌病。这些发现，再加上以前的研究肌球蛋白轻链的结构和功能在心脏，建议功能丧失疾病mechanism. Conclusions不同的突变影响相同的肌节蛋白可以导致显性或隐性心肌病。在杂合状态下，高度保守氨基酸的静电电荷逆转可能是良性的，这是保护心脏结构和功能的代偿机制的结果。相比之下，肌节蛋白缺陷的纯合子携带者可能具有恶性病程。认识到隐性遗传的儿童心肌病是必要的适当的家庭咨询。
Background-Autosomal dominant hypertrophic cardiomyopathy (HCM) is caused by inherited defects of safcomeric proteins. We tested the hypothesis that hornozygosity for a sarcomeric protein defect can cause recessive HCM.Methods and Results-We studied a family with early-onset cardiomyopathy in 3 siblings, characterized by mid-cavitary hypertrophy and restrictive physiology. Genotyping of DNA markers spanning 8 genes for autosomal dominant HCM revealed inheritance of an identical paternal and maternal haplotype at the essential light chain of myosin locus by the affected children. Sequencing showed that these individuals were homozygous for a Glu143Lys substitution of a highly conserved amino acid that was absent in 150 controls. Family members with one Glu143Lys allele had normal echocardiograms and ECGs, even in late adulthood, whereas those with two mutant alleles developed severe cardiomyopathy in childhood. These findings, coupled with previous studies of myosin light chain structure and function in the heart, suggest a loss-of-function disease mechanism.Conclusions-Distinct mutations affecting the same sarcomeric protein can cause either dominant or recessive cardiomyopathy. Electrostatic charge reversal of a highly conserved amino acid may be benign in the heterozygous state as the result of compensatory mechanisms that preserve cardiac structure and function. By contrast, homozygous carriers of a sarcomeric protein defect may have a malignant course. Recognizing recessive inheritance in children with cardiomyopathy is essential for appropriate family counseling.