Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant.

TitleNemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant.
Publication TypeJournal Article
Year of Publication2018
AuthorsSandaradura, SA, Bournazos, A, Mallawaarachchi, A, Cummings, BB, Waddell, LB, Jones, KJ, Troedson, C, Sudarsanam, A, Nash, BM, Peters, GB, Algar, EM, MacArthur, DG, North, KN, Brammah, S, Charlton, A, Laing, NG, Wilson, MJ, Davis, MR, Cooper, ST
JournalHum Mutat
Date Published2018 03
KeywordsArthrogryposis, Genes, Recessive, Humans, Infant, Infant, Newborn, Male, Myopathies, Nemaline, RNA Splice Sites, RNA Splicing, RNA, Messenger, Troponin T

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 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 protein with secondary loss of troponin-I . We establish a homozygous splice variant in TNNT3 as the likely cause of severe congenital NM with distal arthrogryposis, characterized by specific involvement of Type-2 fibers and deficiency of troponin-T .

Alternate JournalHum. Mutat.
PubMed ID29266598
PubMed Central IDPMC5805634
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States