ClinVar

In affected individuals with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355), also known as Amish nemaline myopathy, Johnston et al. (2000) identified a homozygous c.579G-T transversion in exon 11 of the TNNT1 gene, resulting in a stop codon at amino acid 180 (E180X) and loss of 83 C-terminal residues. Johnston et al. (2000) had treated or obtained clinical information on 71 infants and young children from 33 nuclear Amish families with this form of nemaline myopathy. In the first months of life, affected infants had tremors with hypotonia and mild contractures of the shoulders and hips. Progressive worsening of the proximal contractures, weakness, and a pectus carinatum deformity developed before the children died of respiratory insufficiency, usually in the second year.

Variant Function

Jin et al. (2003) found complete loss of the TNNT1 protein in patients with the E180X mutation. The truncated protein results in elimination of the C-terminal T2 domain that interacts with troponin C (TNNC1; 191040), I (TNNI2; 191043), and tropomyosin (TPM1; 191010), but was predicted to retain a central tropomyosin-binding site that participates in the anchoring of troponin complex to the thin actin filament. If residual truncated protein was produced, this could potentially result in a dominant-negative effect. The significant muscle atrophy observed in the disorder was consistent with the slow Tnt isoform being involved in muscle development and growth.

In a patient with Amish nemaline myopathy due to the E180X mutation, Wang et al. (2005) detected residual mutant TNNT1 mRNA in muscle tissue but no corresponding translated mutant TNNT1 protein. In vitro functional expression studies in nonmuscle cells showed that E180X-mutant protein could be produced but was not detectable when expressed in muscle cells in vitro. The findings suggested rapid degradation of E180X-mutant protein in muscle cells, rather than a loss of nonsense mRNA to explain the absence of a dominant effect. Wang et al. (2005) postulated that inefficient incorporation of mutant TNNT1 into myofilaments results in its degradation by the muscle cell as a protective mechanism.