Disruption of heart sarcoglycan complex and severe cardiomyopathy caused by beta sarcoglycan mutations

Two young males with limb-girdle muscular dystrophy (LGMD) resulting from s arcoglycan deficiency died at 27 (patient 1) and 18 years (patient 2) of se vere cardiomyopathy. Genetic analysis showed that they were compound hetero zygotes 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 mut ation 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 mus cle defects with faster deterioration; no sarcoglycans were detected in his skeletal muscle. The second mutation in patient 1, inferred because the un affected father carries the 8 bp duplication, was not found. in patient I,b oth heart and skeletal muscle were analysed and showed reduction of all sar coglycans in both tissues and incorrect localisation of alpha and gamma sar coglycans ire heart. Therefore mutations in one sarcoglycan gene can disrup t the entire sarcoglycan complex in both skeletal and cardiac muscle. Diffe ring expression patterns of sarcoglycan components in heart and skeletal mu scle could be the result of alternatively spliced transcripts in these tiss ues. By sequencing an alternative transcript, highly expressed in the heart and skeletal muscle of patient 1, we found an 87 bp cryptic exon not previ ously 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 there fore expands the phenotype of sarcoglycanopathies and suggests that cardiac function in LGMD patients with defective sarcoglycan expression should be monitored.