Disruption of heart sarcoglycan complex and severe cardiomyopathy caused by beta sarcoglycan mutations.
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 1, both heart and skeletal muscle were analysed and showed reduction of all sarcoglycans in both tissues and incorrect localisation of alpha and gamma sarcoglycans in 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 can 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.
Barresi
R
R
Department of Neuromuscular Diseases, Istituto Nazionale Neurologico "C Besta", Via Celoria 11, 20133 Milano, Italy.
Di Blasi
C
C
Negri
T
T
Brugnoni
R
R
Vitali
A
A
Felisari
G
G
Salandi
A
A
Daniel
S
S
Cornelio
F
F
Morandi
L
L
Mora
M
M
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D009202:Cardiomyopathies / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D049030:Dystroglycans; D016189:Dystrophin / Q000235:genetics; D005091:Exons; D017809:Fatal Outcome; D005260:Female; D020440:Gene Duplication; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D009136:Muscular Dystrophies / Q000235:genetics*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype
D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D016189:Dystrophin; D008562:Membrane Glycoproteins; D049030:Dystroglycans