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Hum Mutat. 2018 Mar;39(3):383-388. doi: 10.1002/humu.23385. Epub 2018 Jan 13.

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

Author information

1
Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
2
Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia.
3
Department of Clinical Genetics, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
4
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.
5
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.
6
Department of Neurology, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
7
Sydney Genome Diagnostics, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
8
Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
9
Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
10
Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
11
Department of Paediatrics, Faculty of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
12
Electron Microscope Unit, Concord Repatriation General Hospital, Sydney, New South Wales, Australia.
13
Department of Anatomical Pathology, Middlemore Hospital, Auckland, New Zealand.
14
Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Perth, Western Australia, Australia.
15
Centre for Medical Research University of Western Australia, Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia.

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 .

KEYWORDS:

TNNT3; genetics; nemaline myopathy; neuromuscular disease; troponin T-fast

PMID:
29266598
PMCID:
PMC5805634
DOI:
10.1002/humu.23385
[Indexed for MEDLINE]
Free PMC Article

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