TPM2 – Congenital Fiber-Type Disproportion Myopathy

Autosomal-dominant variants in TPM2 are established causes of congenital fiber-type disproportion myopathy (CFTD), a disorder marked by early-onset generalized weakness, hypotonia, and disproportionate type-I fiber predominance (PMID:24692096). Affected individuals often present in infancy with delayed motor milestones and persistently reduced muscle tone.

In a cohort of 53 unrelated families harboring TPM2 mutations, thirty distinct pathogenic variants were identified, the majority being heterozygous missense changes consistent with an autosomal-dominant inheritance pattern (PMID:24692096). Segregation analysis demonstrated co-segregation of these variants with CFTD in at least 19 additional affected relatives across multiple pedigrees. The variant spectrum includes 25 missense substitutions, three small in-frame deletions, and two canonical splice-site alterations. A representative allele is c.121G>A (p.Glu41Lys), recurrently observed in CFTD and nemaline myopathy presentations (PMID:22084935).

Functional studies elucidate a dominant-negative or gain-of-function mechanism. The p.Glu41Lys variant “freezes” tropomyosin in an off-state on actin, reducing Ca²⁺ sensitivity and limiting strong myosin–actin interactions in polarized fluorescence assays (PMID:29792862). In vivo overexpression of dominant TPM2 alleles, including p.Ala155Thr and p.Glu139Lys, disrupts myotube morphogenesis in zebrafish and Drosophila and correlates with clinical severity (PMID:35579956). Biochemical binding assays for variants such as p.Lys7del and p.Gln147Pro demonstrate impaired tropomyosin–actin affinity, further supporting pathogenicity (PMID:23378224).

No studies have refuted this association. Concordance between genetic segregation, multiple independent functional assays, and phenotypic overlap across congenital myopathies establishes a robust gene–disease relationship. Additional structure–function data elaborate variant-specific effects on thin-filament activation, although these exceed current ClinGen functional scoring caps.

Key take-home: Heterozygous TPM2 mutations cause autosomal-dominant congenital fiber-type disproportion myopathy via perturbation of thin-filament regulation, guiding molecular diagnosis and highlighting thin-filament Ca²⁺-sensitivity modulators as potential therapeutic targets.

References

• Human mutation • 2014 • Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies. PMID:24692096
• Brain : a journal of neurology • 2013 • K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity. PMID:23378224
• Biochemical and biophysical research communications • 2018 • The reason for the low Ca2+-sensitivity of thin filaments associated with the Glu41Lys mutation in the TPM2 gene is "freezing" of tropomyosin near the outer domain of actin and inhibition of actin monomer switching off during the ATPase cycle. PMID:29792862
• JCI insight • 2022 • A pathogenic mechanism associated with myopathies and structural birth defects involves TPM2-directed myogenesis. PMID:35579956

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