Arbustini Eloisa, Pilotto Andrea, Repetto Alessandra, Grasso Maurizia, Negri Andrea, Diegoli Marta, Campana Carlo, Scelsi Laura, Baldini Elisa, Gavazzi Antonello, Tavazzi Luigi
Molecular Diagnostic Division, IRCCS Policlinico San Matteo, Pavia, Italy.
J Am Coll Cardiol. 2002 Mar 20;39(6):981-90. doi: 10.1016/s0735-1097(02)01724-2.
We investigated the prevalence of lamin A/C (LMNA) gene defects in familial and sporadic dilated cardiomyopathies (DCM) associated with atrioventricular block (AVB) or increased serum creatine-phosphokinase (sCPK), and the corresponding changes in myocardial and protein expression.
It has been reported that familial DCM, associated with conduction disturbances or variable myopathies, is causally linked to LMNA gene defects.
The LMNA gene and myocardial ultrastructural and immunochemical changes were analyzed in 73 cases of DCM (49 pure, 15 with AVB [seven familial, eight sporadic], 9 with increased sCPK), four cases of familial AVB and 19 non-DCM heart diseases. The normal controls included eight heart donor biopsies for tissue studies and 107 subjects for LMNA gene studies.
Five novel LMNA mutations (K97E, E111X, R190W, E317K, four base pair insertion at 1,713 cDNA) were identified in five cases of familial autosomal dominant DCM with AVB (5/15: 33%). The LMNA expression of the myocyte nuclei was reduced or absent. Western blot protein analyses of three hearts with different mutations showed an additional 30-kDa band, suggesting a degrading effect of mutated on wild-type protein. Focal disruptions, bleb formation and nuclear pore clustering were documented by electron microscopy of the myocyte nuclear membranes. None of these changes and no mutations were found in the nine patients with DCM and increased sCPK or in the disease and normal controls.
The LMNA gene mutations account for 33% of the DCMs with AVB, all familial autosomal dominant. Increased sCPK in patients with DCM without AVB is not a useful predictor of LMNA mutation.
我们研究了与房室传导阻滞（AVB）或血清肌酸磷酸激酶（sCPK）升高相关的家族性和散发性扩张型心肌病（DCM）中核纤层蛋白A/C（LMNA）基因缺陷的患病率，以及心肌和蛋白表达的相应变化。
据报道，与传导障碍或多种肌病相关的家族性DCM与LMNA基因缺陷存在因果关系。
对73例DCM患者（49例单纯型、15例合并AVB[7例家族性、8例散发性]、9例sCPK升高）、4例家族性AVB患者和19例非DCM心脏病患者进行了LMNA基因及心肌超微结构和免疫化学变化分析。正常对照包括8例用于组织研究的心脏供体活检组织和107例用于LMNA基因研究的受试者。
在5例伴有AVB的家族性常染色体显性DCM患者中（5/15：33%）鉴定出5种新的LMNA突变（K97E、E111X、R190W、E317K、cDNA 1713处4个碱基对插入）。心肌细胞核的LMNA表达降低或缺失。对3例具有不同突变的心脏进行的蛋白质免疫印迹分析显示有一条额外的30 kDa条带，提示突变对野生型蛋白有降解作用。通过心肌细胞核膜的电子显微镜观察记录到局灶性破坏、小泡形成和核孔聚集。在9例DCM且sCPK升高的患者以及疾病和正常对照中均未发现这些变化及突变。
LMNA基因突变占伴有AVB的DCM的33%，均为家族性常染色体显性。无AVB的DCM患者sCPK升高并非LMNA突变的有效预测指标。
