TPM3 – congenital fiber-type disproportion myopathy

TPM3 encodes the slow skeletal muscle α-tropomyosin and is implicated in autosomal dominant congenital fiber-type disproportion myopathy (TPM3; congenital fiber-type disproportion myopathy). CFTD is defined by selective type 1 fiber hypotrophy of at least 12% without other structural lesions, leading to muscle weakness and hypotonia.

In a cohort of 23 unrelated CFTD probands, sequencing of TPM3 identified novel heterozygous missense variants in six families, all cosegregating with disease and histologically confirmed type 1 fiber atrophy (PMID:18300303). Affected individuals exhibited proximal limb girdle and neck flexor weakness, ankle dorsiflexion deficits, mild facial involvement, and occasional ptosis.

The variant spectrum spans eight missense substitutions clustering in exons 5–8, including c.298C>A (p.Leu100Met) and recurrent mutations at Arg168 (p.Arg168Gly/Cys/His), as well as a rare nonsense allele p.Gln32Ter (PMID:18300303).

Biochemical and cellular assays demonstrate that TPM3 mutations impair tropomyosin–actin binding, reduce Ca²⁺-sensitivity, and disrupt thin filament activation. Co-sedimentation and in vitro motility studies reproduce the slow fiber hypotrophy phenotype observed in patient biopsies (PMID:19953533; PMID:26307083).

Although congenital myotonic dystrophy due to DMPK expansions can mimic CFTD histology, TPM3 mutation screening differentiates primary TPM3‐related CFTD from secondary causes (PMID:20179953).

Collectively, robust genetic segregation in multiple pedigrees and concordant functional data establish TPM3 as a definitive CFTD gene. TPM3 testing is recommended in patients with type 1 fiber disproportion to inform diagnosis, genetic counseling, and potential Ca²⁺-sensitizing therapeutic strategies.

References

• Annals of neurology • 2008 • Mutations in TPM3 are a common cause of congenital fiber type disproportion PMID:18300303
• Human mutation • 2010 • Mutations of tropomyosin 3 (TPM3) are common and associated with type 1 myofiber hypotrophy in congenital fiber type disproportion PMID:19953533
• Human molecular genetics • 2015 • Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres PMID:26307083
• Acta neuropathologica • 2010 • Congenital myotonic dystrophy can show congenital fiber type disproportion pathology PMID:20179953

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