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

Sarah A. Sandaradura, Adam Bournazos, Amali Mallawaarachchi, Beryl B. Cummings, Leigh B. Waddell, Kristi J. Jones, Christopher Troedson, Annapurna Sudarsanam, Benjamin M. Nash, Gregory B. Peters, Elizabeth M. Algar, Daniel G. Macarthur, Kathryn N. North, Susan Brammah, Amanda Charlton, Nigel G. Laing, Meredith J. Wilson, Mark R. Davis, Sandra T. Cooper

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Abstract

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-Tfast 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-Tfast protein with secondary loss of troponin-Ifast. 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-Tfast.

Original languageEnglish
Pages (from-to)383-388
JournalHuman Mutation
Volume39
Issue number3
DOIs
Publication statusPublished - Mar 2018

Fingerprint

Nemaline Myopathies
Arthrogryposis
Troponin
Myotonia Congenita
Muscle Hypotonia
Scoliosis
Contracture
Introns
Hypertrophy
Atrophy
Exons
Skeletal Muscle
Proteins
Complementary DNA
Western Blotting
Genes

Cite this

Sandaradura, S. A., Bournazos, A., Mallawaarachchi, A., Cummings, B. B., Waddell, L. B., Jones, K. J., ... Cooper, S. T. (2018). Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant. Human Mutation, 39(3), 383-388. https://doi.org/10.1002/humu.23385
Sandaradura, Sarah A. ; Bournazos, Adam ; Mallawaarachchi, Amali ; Cummings, Beryl B. ; Waddell, Leigh B. ; Jones, Kristi J. ; Troedson, Christopher ; Sudarsanam, Annapurna ; Nash, Benjamin M. ; Peters, Gregory B. ; Algar, Elizabeth M. ; Macarthur, Daniel G. ; North, Kathryn N. ; Brammah, Susan ; Charlton, Amanda ; Laing, Nigel G. ; Wilson, Meredith J. ; Davis, Mark R. ; Cooper, Sandra T. / Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant. In: Human Mutation. 2018 ; Vol. 39, No. 3. pp. 383-388.
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abstract = "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-Tfast 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-Tfast protein with secondary loss of troponin-Ifast. 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-Tfast.",
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Sandaradura, 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 2018, 'Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant' Human Mutation, vol. 39, no. 3, pp. 383-388. https://doi.org/10.1002/humu.23385

Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant. / Sandaradura, Sarah A.; Bournazos, Adam; Mallawaarachchi, Amali; Cummings, Beryl B.; Waddell, Leigh B.; Jones, Kristi J.; Troedson, Christopher; Sudarsanam, Annapurna; Nash, Benjamin M.; Peters, Gregory B.; Algar, Elizabeth M.; Macarthur, Daniel G.; North, Kathryn N.; Brammah, Susan; Charlton, Amanda; Laing, Nigel G.; Wilson, Meredith J.; Davis, Mark R.; Cooper, Sandra T.

In: Human Mutation, Vol. 39, No. 3, 03.2018, p. 383-388.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant

AU - Sandaradura, Sarah A.

AU - Bournazos, Adam

AU - Mallawaarachchi, Amali

AU - Cummings, Beryl B.

AU - Waddell, Leigh B.

AU - Jones, Kristi J.

AU - Troedson, Christopher

AU - Sudarsanam, Annapurna

AU - Nash, Benjamin M.

AU - Peters, Gregory B.

AU - Algar, Elizabeth M.

AU - Macarthur, Daniel G.

AU - North, Kathryn N.

AU - Brammah, Susan

AU - Charlton, Amanda

AU - Laing, Nigel G.

AU - Wilson, Meredith J.

AU - Davis, Mark R.

AU - Cooper, Sandra T.

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N2 - 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-Tfast 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-Tfast protein with secondary loss of troponin-Ifast. 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-Tfast.

AB - 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-Tfast 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-Tfast protein with secondary loss of troponin-Ifast. 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-Tfast.

KW - Genetics

KW - Nemaline myopathy

KW - Neuromuscular disease

KW - TNNT3

KW - Troponin T-fast

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Sandaradura SA, Bournazos A, Mallawaarachchi A, Cummings BB, Waddell LB, Jones KJ et al. Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant. Human Mutation. 2018 Mar;39(3):383-388. https://doi.org/10.1002/humu.23385