TNNT1 – Nemaline Myopathy

The slow skeletal muscle troponin T gene TNNT1 encodes the tropomyosin‐binding component of the troponin complex essential for thin‐filament regulation. Biallelic or monoallelic pathogenic variants in TNNT1 cause nemaline myopathy, a congenital myopathy marked by sarcomeric rod inclusions, hypotonia, and muscle weakness.

Inheritance is predominantly autosomal recessive, with multiple unrelated cases harboring homozygous nonsense or compound heterozygous truncating and splice‐site mutations. A non‐Amish Hispanic male was homozygous for a nonsense variant c.323C>G (p.Ser108Ter) (PMID:25430424), and two Italian siblings carried a novel homozygous missense change (PMID:31604653). Rare autosomal dominant missense variants (eg, c.311A>T (p.Glu104Val)) segregate in large pedigree(s) with dominant‐negative effects (PMID:29178646).

The variant spectrum includes over 15 distinct pathogenic alleles: nonsense (c.323C>G (p.Ser108Ter)), frameshift (c.587dupA (p.Asp196GlufsTer41)), splice‐site (c.611+1G>A), and missense changes (c.724G>C (p.Ala242Pro) (PMID:35165004), c.194A>C (p.Asp65Ala) (PMID:35510366)). These occur across diverse populations, with recurrent founder mutations in Amish and non‐Amish cohorts.

Functional studies in zebrafish demonstrate that human missense and splice variants (c.724G>C and c.611+1G>A) fail to rescue tnnt1 morphant phenotypes, supporting loss‐of‐function (PMID:35165004). Cellular assays reveal rapid degradation of truncated TnT at Glu180 and absence of stable incorporation into filaments (PMID:15665378). Dominant‐negative assembly defects for p.Glu104Val disrupt tropomyosin interactions (PMID:29178646).

Clinical presentation in recessive TNNT1 nemaline myopathy often includes severe neonatal hypotonia (HP:0001252), respiratory insufficiency (HP:0002093), and feeding difficulties, sometimes with pectus carinatum and early contractures (PMID:31604653). Autosomal dominant cases exhibit milder, slowly progressive muscle weakness (HP:0001324) without early respiratory compromise (PMID:29178646).

No conflicting evidence has been reported to refute the TNNT1–nemaline myopathy association. Both loss‐of‐function and dominant‐negative mechanisms are consistent with genotype–phenotype correlations across multiple studies.

Integration of genetic and experimental data supports a Strong clinical validity for TNNT1 nemaline myopathy. TNNT1 should be included in diagnostic panels for congenital myopathies, with early genetic confirmation guiding management of respiratory and orthopedic complications.

References

• Muscle & nerve • 2015 • Identification of a novel nemaline myopathy-causing mutation in the troponin T1 (TNNT1) gene: a case outside of the old order Amish. PMID:25430424
• Molecular genetics & genomic medicine • 2017 • Novel autosomal dominant TNNT1 mutation causing nemaline myopathy. PMID:29178646
• Neuromuscular disorders • 2022 • TNNT1 myopathy with novel compound heterozygous mutations. PMID:35165004
• Annals of neurology • 2020 • Novel Recessive TNNT1 Congenital Core-Rod Myopathy in French Canadians. PMID:31970803
• Journal of human genetics • 2023 • Exon skipping caused by splicing mutation in TNNT1 nemaline myopathy. PMID:36446828
• Neuromuscular disorders • 2019 • ‘Amish Nemaline Myopathy’ in 2 Italian siblings harbouring a novel homozygous mutation in Troponin-I gene. PMID:31604653
• Muscle & nerve • 2016 • Nemaline body myopathy caused by a novel mutation in troponin T1 (TNNT1). PMID:26296490
• The 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
• Genes & genomics • 2024 • A rare TNNT1 gene variant causing creatine kinase elevation in nemaline myopathy: c.271_273del (p.Lys91del). PMID:38363456

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