Hypertrophic cardiomyopathy caused by a novel alpha-tropomyosin mutation (V95A) is associated with mild cardiac phenotype, abnormal calcium binding to troponin, abnormal myosin cycling, and poor prognosis.
Hypertrophic cardiomyopathy caused by a novel alpha-tropomyosin mutation (V95A) is associated with mild cardiac phenotype, abnormal calcium binding to troponin, abnormal myosin cycling, and poor prognosis.
复制标题
由新型 α-原肌球蛋白突变 (V95A) 引起的肥厚性心肌病与轻度心脏表型、钙与肌钙蛋白结合异常、肌球蛋白循环异常和预后不良相关。
DOI：
10.1161/01.cir.103.1.65
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发表时间：
2001
期刊：
影响因子：
37.8
通讯作者：
Fananapazir,L
中科院分区：
文献类型：
--
作者：
Karibe,A;Tobacman,LS;Strand,J;Butters,C;Back,N;Bachinski,LL;Arai,AE;Ortiz,A;Roberts,R;Homsher,E;Fananapazir,L
背景--我们报道了一个由新的α-原肌球蛋白（TPM 1）突变引起的西班牙裔美国人家族的肥厚型心肌病（HCM），并通过鉴定纯化的突变蛋白的功能缺陷来研究该临床疾病的发病机制。方法和结果--HCM与TPM 1基因相关（比值对数[LOD]得分为3.17）。测序和酶切分析证实了一个与HCM共分离的TPM 1突变V95 A。该突变与26名受影响成员中的13例死亡相关（11例猝死，2例与心力衰竭相关），40岁时的累积生存率为73±10%。左室壁厚度（平均16±6 mm）和疾病转移率（53%）与先前与良性预后相关的β-肌球蛋白突变L908 V和G256 E相似。左心室肥厚比β-肌球蛋白突变R403 Q患者轻，但预后同样差。使用重组原肌球蛋白，我们确定了几个功能的改变，在蛋白质水平。该突变引起了40%至50%的钙亲和力增加，在调节薄的顺应性肌球蛋白亚片段-1（S1）MgATP酶测定，在饱和钙的存在下，MgATP酶速率下降20%，在体外运动性测定中，无负荷缩短速度下降5%，并且没有改变合作肌球蛋白S1结合到调节细丝。V95 A相关的HCM表现出轻微的表型，但预后不良的不寻常的特点。肌球蛋白循环和钙结合肌钙蛋白是异常的突变原肌球蛋白的存在。这种突变提供的基因诊断将是有价值的HCM的管理。
Background—We report hypertrophic cardiomyopathy (HCM) in a Spanish-American family caused by a novel α-tropomyosin (TPM1)mutation and examine the pathogenesis of the clinical disease by characterizing functional defects in the purified mutant protein.Methods and Results—HCM was linked to theTPM1gene (logarithm of the odds [LOD] score 3.17). Sequencing and restriction digestion analysis demonstrated aTPM1mutation V95A that cosegregated with HCM. The mutation has been associated with 13 deaths in 26 affected members (11 sudden deaths and 2 related to heart failure), with a cumulative survival rate of 73±10% at the age of 40 years. Left ventricular wall thickness (mean 16±6 mm) and disease penetrance (53%) were similar to those for the β-myosin mutations L908V and G256E previously associated with a benign prognosis. Left ventricular hypertrophy was milder than with the β-myosin mutation R403Q, but the prognosis was similarly poor. With the use of recombinant tropomyosins, we identified several functional alterations at the protein level. The mutation caused a 40% to 50% increase in calcium affinity in regulated thin filament–myosin subfragment-1 (S1) MgATPase assays, a 20% decrease in MgATPase rates in the presence of saturating calcium, a 5% decrease in unloaded shortening velocity in in vitro motility assays, and no change in cooperative myosin S1 binding to regulated thin filaments.Conclusions—In contrast to other reportedTPM1mutations, V95A-associated HCM exhibits unusual features of mild phenotype but poor prognosis. Both myosin cycling and calcium binding to troponin are abnormal in the presence of the mutant tropomyosin. The genetic diagnosis afforded by this mutation will be valuable in the management of HCM.