TPM3 – Nemaline Myopathy

TPM3, encoding slow skeletal muscle α-tropomyosin, is a well-established cause of nemaline myopathy when mutated in either autosomal dominant or recessive configurations. Pathogenic variants cluster in constitutively expressed exons and disrupt thin filament regulation, leading to characteristic nemaline rod inclusions and muscle weakness. The association is supported by multiple unrelated probands, segregation in families, and concordant functional studies.

Autosomal dominant inheritance predominates, with several de novo and inherited missense variants identified. A de novo c.503G>A (p.Arg168His) variant in exon 5 was reported in a sporadic late-onset case presenting with kyphoscoliosis (PMID:12467750). A novel p.Ala156Thr substitution segregated in a German kindred with autosomal dominant nemaline myopathy and muscle MRI correlates (PMID:20012312).

Recessive loss-of-function alleles have been described in rare early-onset cases. Compound heterozygous splice-site variants NM_152263.4:c.117+2_5delTAGG and c.117+1>T markedly reduce TPM3 protein expression in a Finnish patient with infantile nemaline myopathy (PMID:37393515), while a homozygous 17-21 kb deletion removing exons 1a–2b produced severe neonatal disease (PMID:27858751).

A Turkish founder frameshift, c.913delA (p.Ter306AsnextTer?), was identified in two unrelated recessive families, causing intermediate to severe phenotypes with characteristic type 1 fiber hypotrophy (PMID:18382475). Overall, reported variant classes include missense, splice-site, nonsense, and copy-number deletions.

Functional assays demonstrate that disease-causing TPM3 variants alter tropomyosin–actin affinity and calcium sensitivity. In vitro motility and thin-filament reconstitution studies of p.Met9Arg show decreased actin binding and reduced Ca²⁺ sensitivity, recapitulating contractile deficits (PMID:10587521; PMID:11106625). Biophysical analyses of multiple missense mutants confirm perturbed coiled-coil stability and impaired troponin regulation (PMID:22749829).

The convergence of genetic and experimental data supports a haploinsufficiency/dominant-negative mechanism whereby mutant tropomyosin disrupts thin-filament regulation, leading to muscle weakness and rod formation. No conflicting evidence has been reported to date.

Key take-home: TPM3 mutations cause both autosomal dominant and recessive nemaline myopathy through altered actin-binding and calcium regulation of thin filaments, with clear diagnostic and therapeutic implications.

References

• Neuromuscular Disorders • 2002 • De novo missense mutation in a constitutively expressed exon of the slow alpha-tropomyosin gene TPM3 associated with an atypical, sporadic case of nemaline myopathy. PMID:12467750
• Neurology • 2002 • Mutations of the slow muscle alpha-tropomyosin gene, TPM3, are a rare cause of nemaline myopathy. PMID:12196661
• Journal of Neuromuscular Diseases • 2023 • Novel Compound Heterozygous Splice-Site Variants in TPM3 Revealed by RNA Sequencing in a Patient with an Unusual Form of Nemaline Myopathy: A Case Report. PMID:37393515
• Journal of Neuromuscular Diseases • 2015 • A Large Deletion Affecting TPM3, Causing Severe Nemaline Myopathy. PMID:27858751
• European Journal of Human Genetics • 2008 • Identification of a founder mutation in TPM3 in nemaline myopathy patients of Turkish origin. PMID:18382475
• The Journal of Clinical Investigation • 1999 • A nemaline myopathy mutation in alpha-tropomyosin causes defective regulation of striated muscle force production. PMID:10587521
• Biochimica et Biophysica Acta • 2012 • Functional effects of congenital myopathy-related mutations in gamma-tropomyosin gene. PMID:22749829

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