TPM2 – TPM2-related Congenital Myopathy

Autosomal-dominant mutations in TPM2 (beta-tropomyosin) cause a spectrum of congenital myopathies characterized by early onset hypotonia and muscle weakness. Clinical and histopathological overlap with nemaline myopathy and cap disease reflects disrupted thin filament architecture and function. TPM2 variants perturb actin binding and tropomyosin dynamics, informing targeted therapeutic strategies.

Clinical Validity

Multiple independent reports describe autosomal-dominant TPM2 variants in 10 unrelated probands across five studies, including de novo and familial segregation, with congruent functional data supporting pathogenicity ([PMID:19047562]). No conflicting evidence has been reported, yielding a Strong gene–disease association.

Genetic Evidence

Inheritance is autosomal dominant. Segregation analysis identified 2 additional affected relatives in one pedigree ([PMID:24507666]). A total of 10 probands harbor heterozygous TPM2 mutations: in-frame deletions (e.g., c.415_417del (p.Glu139del)), missense substitutions, splice-site changes, and premature stops. Recurrent variants include p.Lys7del and p.Glu41Lys. Carrier frequency data are unavailable but the rarity of these variants in population databases supports pathogenicity.

Functional Evidence

TPM2 mutations alter tropomyosin–actin interactions by reducing thin filament Ca2+-sensitivity, impairing troponin-mediated regulation, or inducing hypercontractile phenotypes. In vitro fiber assays demonstrate defective activation and force generation for p.Glu181Lys and rescue by troponin activators ([PMID:22798622]). Drosophila and mouse models expressing patient TPM2 variants recapitulate muscle development defects, confirming a dominant-negative mechanism ([PMID:35579956]).

Integration and Conclusion

Genetic and experimental data converge on TPM2 haploinsufficiency and dominant-negative effects disrupting thin filament regulation in congenital myopathy. Functional assays reveal mutation-specific mechanisms, suggesting precision therapy with thin filament modulators. Key take-home: TPM2 genetic testing guides diagnosis, prognostication, and potential targeted treatment for congenital myopathy.

References

• Neurology • 2008 • New morphologic and genetic findings in cap disease associated with beta-tropomyosin (TPM2) mutations. PMID:19047562
• Neuromuscular Disorders • 2014 • Frequency and phenotype of patients carrying TPM2 and TPM3 gene mutations in a cohort of 94 patients with congenital myopathy. PMID:24507666
• Neuromuscular Disorders • 2014 • Congenital myopathies with secondary neuromuscular transmission defects; a case report and review of the literature. PMID:25127990
• Human Molecular Genetics • 2012 • Congenital myopathy-causing tropomyosin mutations induce thin filament dysfunction via distinct physiological mechanisms. PMID:22798622
• Neuromuscular Disorders • 2021 • Homozygous intronic variants in TPM2 cause recessively inherited Escobar variant of multiple pterygium syndrome and congenital myopathy. PMID:33558124

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