Disruption of heart sarcoglycan complex and severe cardiomyopathy caused by β sarcoglycan mutations
Disruption of heart sarcoglycan complex and severe cardiomyopathy caused by β sarcoglycan mutations
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DOI：
10.1136/jmg.37.2.102
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发表时间：
2000-02-01
影响因子：
4
通讯作者：
Mora, M
中科院分区：
文献类型：
--
作者：
Barresi, R;Di Blasi, C;Mora, M
两名患有肌聚糖缺乏引起的肢带型肌营养不良症（LGMD）的年轻男性分别在27岁（患者1）和18岁（患者2）死于严重心肌病。遗传学分析表明，他们是β-肌聚糖基因突变的复合杂合子，其中一个突变，外显子3的8bp重复，是两例患者共有的。患者2的第二个突变是内含子2剪接供体位点的4 bp缺失，以前未报道。患者2有更严重的心脏和骨骼肌缺陷，恶化更快;在他的骨骼肌中没有检测到肌聚糖。第二个突变在患者1中，推断是因为未受影响的父亲携带8 bp的重复，没有发现。在患者I中，心脏和骨骼肌都进行了分析，并显示在两种组织中的所有肌聚糖减少和不正确的定位α和γ肌聚糖的心脏。因此，一个肌聚糖基因的突变可以破坏骨骼肌和心肌中的整个肌聚糖复合体。在心脏和骨骼肌中肌聚糖组分的不同表达模式可能是这些组织中选择性剪接转录的结果。通过对一个在患者1的心脏和骨骼肌中高度表达的替代转录物进行测序，我们发现了一个先前未报道的87 bp的隐藏外显子。虽然心肌病是由α和γ肌聚糖突变引起的，但我们首次表明这种疾病也可能是由β肌聚糖基因突变引起的。因此，本报告扩大了肌聚糖病的表型，并建议应监测肌聚糖表达缺陷的LGMD患者的心脏功能。
Two young males with limb-girdle muscular dystrophy (LGMD) resulting from sarcoglycan deficiency died at 27 (patient 1) and 18 years (patient 2) of severe cardiomyopathy. Genetic analysis showed that they were compound heterozygotes for mutations in the beta sarcoglycan gene, One of these mutations, an 8 bp duplication in exon 3, was common to both patients. The second mutation in patient 2 was a 4 bp deletion at the splice donor site of intron 2, not reported previously. Patient 2 had more severe heart and skeletal muscle defects with faster deterioration; no sarcoglycans were detected in his skeletal muscle. The second mutation in patient 1, inferred because the unaffected father carries the 8 bp duplication, was not found. in patient I,both heart and skeletal muscle were analysed and showed reduction of all sarcoglycans in both tissues and incorrect localisation of alpha and gamma sarcoglycans ire heart. Therefore mutations in one sarcoglycan gene can disrupt the entire sarcoglycan complex in both skeletal and cardiac muscle. Differing expression patterns of sarcoglycan components in heart and skeletal muscle could be the result of alternatively spliced transcripts in these tissues. By sequencing an alternative transcript, highly expressed in the heart and skeletal muscle of patient 1, we found an 87 bp cryptic exon not previously reported. Although cardiomyopathy earn result from mutations in alpha and gamma sarcoglycans, we show for the first time that the condition can also be caused by mutations in the beta sarcoglycan gene. This report therefore expands the phenotype of sarcoglycanopathies and suggests that cardiac function in LGMD patients with defective sarcoglycan expression should be monitored.