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Mol Genet Genomic Med. 2017 Nov;5(6):678-691. doi: 10.1002/mgg3.325. Epub 2017 Aug 21.

Novel autosomal dominant TNNT1 mutation causing nemaline myopathy.

Author information

1
Department of Neurosciences, University of California San Diego, San Diego, California.
2
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
3
Broad Institute of Harvard University and MIT, Cambridge, Massachusetts.
4
Prevention Genetics, Marshfield, Wisconsin.
5
Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
6
Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, and Clement J. Zablocki VAMC, Milwaukee, Wisconsin.

Abstract

BACKGROUND:

Nemaline myopathy (NEM) is one of the three major forms of congenital myopathy and is characterized by diffuse muscle weakness, hypotonia, respiratory insufficiency, and the presence of nemaline rod structures on muscle biopsy. Mutations in troponin T1 (TNNT1) is 1 of 10 genes known to cause NEM. To date, only homozygous nonsense mutations or compound heterozygous truncating or internal deletion mutations in TNNT1 gene have been identified in NEM. This extended family is of historical importance as some members were reported in the 1960s as initial evidence that NEM is a hereditary disorder.

METHODS:

Proband and extended family underwent Sanger sequencing for TNNT1. We performed RT-PCR and immunoblot on muscle to assess TNNT1 RNA expression and protein levels in proband and father.

RESULTS:

We report a novel heterozygous missense mutation of TNNT1 c.311A>T (p.E104V) that segregated in an autosomal dominant fashion in a large family residing in the United States. Extensive sequencing of the other known genes for NEM failed to identify any other mutant alleles. Muscle biopsies revealed a characteristic pattern of nemaline rods and severe myofiber hypotrophy that was almost entirely restricted to the type 1 fiber population.

CONCLUSION:

This novel mutation alters a residue that is highly conserved among vertebrates. This report highlights not only a family with autosomal dominant inheritance of NEM, but that this novel mutation likely acts via a dominant negative mechanism.

KEYWORDS:

TNNT1 ; Congenital myopathy; nemaline myopathy; troponin T1

PMID:
29178646
PMCID:
PMC5702563
DOI:
10.1002/mgg3.325
[Indexed for MEDLINE]
Free PMC Article

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