TNNT1 – Nemaline Myopathy 5

Autosomal recessive nemaline myopathy 5 (NM5) is caused by biallelic loss-of-function variants in TNNT1, encoding slow skeletal muscle troponin T. Affected infants present with congenital hypotonia, diffuse muscle weakness, nemaline rod inclusions, and progressive respiratory insufficiency consistent with AR inheritance. Dilated cardiomyopathy may co-occur in the setting of contiguous TNNT1–TNNI3 deletions, but classical NM5 lacks primary cardiac involvement. ([PMID:30395933])

To date, six pathogenic TNNT1 variants have been reported in five unrelated Amish and non-Amish families, and an additional homozygous multi-exonic deletion was described in a Mennonite child, yielding at least seven probands with NM5. All variants are truncating or disrupt tropomyosin-binding, consistent with loss of function, and include c.538G>T (p.Glu180Ter). ([PMID:30395933])

Segregation data demonstrate consistent cosegregation of recessive TNNT1 alleles with disease in multiple kindreds. The recurrence of null alleles in unrelated families and absence in population controls support pathogenicity of biallelic TNNT1 loss. ([PMID:15665378])

Functional assays of the truncating p.Glu180Ter variant show rapid proteasomal degradation of mutant TnT and failure to incorporate into myofilaments, leading to deficient tropomyosin binding. ([PMID:15665378]) Additional characterization of non-Amish TNNT1 mutants confirmed impaired tropomyosin-binding at sites 1 and 2 and disrupted thin filament anchoring. ([PMID:27429059]) Zebrafish tnnt1 morphant models are rescued by wild-type but not mutant human TNNT1 mRNA, validating in vivo pathogenicity. ([PMID:31970803])

The mechanism of disease is loss of TnT function in fast and slow skeletal muscle sarcomeres, resulting in nemaline rod formation, fiber hypotrophy, and respiratory failure. The consistent phenotype across ethnicities and robust functional concordance fulfil ClinGen criteria for a Moderate gene–disease association.

Key Take-home: Biallelic truncating or splice variants in TNNT1 cause a severe autosomal recessive nemaline myopathy, and genetic testing for TNNT1 should be prioritized in infants with congenital hypotonia and nemaline rod–positive biopsies.

References

• European journal of medical genetics • 2019 • Amish nemaline myopathy and dilated cardiomyopathy caused by a homozygous contiguous gene deletion of TNNT1 and TNNI3 in a Mennonite child. PMID:30395933
• Journal of biological chemistry • 2005 • Cellular fate of truncated slow skeletal muscle troponin T produced by Glu180 nonsense mutation in amish nemaline myopathy. PMID:15665378
• Biochemistry • 2016 • Functional Basis of Three New Recessive Mutations of Slow Skeletal Muscle Troponin T Found in Non-Amish TNNT1 Nemaline Myopathies. PMID:27429059
• Annals of neurology • 2020 • Novel Recessive TNNT1 Congenital Core-Rod Myopathy in French Canadians. PMID:31970803
• Frontiers in physiology • 2016 • Protein Structure-Function Relationship at Work: Learning from Myopathy Mutations of the Slow Skeletal Muscle Isoform of Troponin T. PMID:27790152

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