Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology
Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology
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DOI：
10.1111/j.1399-0004.2008.01062.x
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发表时间：
2008-11-01
影响因子：
3.5
通讯作者：
Olson, T. M.
中科院分区：
文献类型：
--
作者：
Menon, S. C.;Michels, V. V.;Olson, T. M.
我们发现了一个独特的常染色体显性遗传性心脏病家族，表现为限制性心肌病（RCM）、肥厚型心肌病（HCM）和扩张型心肌病（DCM），并试图确定引发不同重塑途径的分子缺陷。对DCM和/或HCM的9个肌节基因的多态性DNA标记进行了检测，以确定与疾病的分离。排除了与8个基因的连锁，但心肌肌钙蛋白T（TNNT 2）标记与疾病表型共分离。TNNT 2的测序确定了一个杂合错义突变，导致I79 N取代，由所有9个受影响的家庭成员继承，但没有6个未受影响的亲属。突变携带者被诊断为RCM（n = 2）、非梗阻性HCM（n = 3）、DCM（n = 2）、混合型心肌病（n = 1）和轻度向心性左心室肥大（n = 1）。先证者的心内膜心肌活检显示非特异性纤维化、心肌细胞肥大，且无肌原纤维紊乱。无论心肌病亚型如何，在家族成员中均观察到限制性多普勒充盈模式、心房扩大和肺动脉高压。肌节蛋白基因突变可导致同一家族中的RCM、HCM和DCM，强调了在家族性心肌病筛查中进行全面的形态学和生理学心脏评估的必要性。
We identified a unique family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), and sought to identify the molecular defect that triggered divergent remodeling pathways. Polymorphic DNA markers for nine sarcomeric genes for DCM and/or HCM were tested for segregation with disease. Linkage to eight genes was excluded, but a cardiac troponin T (TNNT2) marker cosegregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution, inherited by all nine affected family members but by none of the six unaffected relatives. Mutation carriers were diagnosed with RCM (n = 2), non-obstructive HCM (n = 3), DCM (n = 2), mixed cardiomyopathy (n = 1), and mild concentric left ventricular hypertrophy (n = 1). Endomyocardial biopsy in the proband revealed non-specific fibrosis, myocyte hypertrophy, and no myofibrillar disarray. Restrictive Doppler filling patterns, atrial enlargement, and pulmonary hypertension were observed among family members regardless of cardiomyopathy subtype. Mutation of a sarcomeric protein gene can cause RCM, HCM, and DCM within the same family, underscoring the necessity of comprehensive morphological and physiological cardiac assessment in familial cardiomyopathy screening.