期刊
HUMAN MUTATION
卷 39, 期 3, 页码 383-388出版社
WILEY
DOI: 10.1002/humu.23385
关键词
genetics; neuromuscular disease; nemaline myopathy; TNNT3; troponin T-fast
资金
- National Health and Medical Research Council [1002147, 1048816, 1075451, 1080587]
- National Heart, Lung, and Blood Institute [UM1 HG008900]
- National Human Genome Research Institute
- National Eye Institute
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R01HG009141, UM1HG008900] Funding Source: NIH RePORTER
A male neonate presented with severe weakness, hypotonia, contractures and congenital scoliosis. Skeletal muscle specimens showed marked atrophy and degeneration of fast fibers with striking nemaline rods and hypertrophy of slow fibers that were ultrastructurally normal. A neuromuscular gene panel identified a homozygous essential splice variant in TNNT3 (chr11:1956150G > A, NM_006757.3:c.681+1G > A). TNNT3 encodes skeletal troponin-T-fast and is associated with autosomal dominant distal arthrogryposis. TNNT3 has not previously been associated with nemaline myopathy (NM), a rare congenital myopathy linked to defects in proteins associated with thin filament structure and regulation. cDNA studies confirmed pathogenic consequences of the splice variant, eliciting exon-skipping and intron retention events leading to a frameshift. Western blot showed deficiency of troponin-T-fast protein with secondary loss of troponin-I-fast. We establish a homozygous splice variant in TNNT3 as the likely cause of severe congenital NM with distal arthro-gryposis, characterized by specific involvement of Type-2 fibers and deficiency of troponin-T-fast.
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