TPM3 – Cap Myopathy

Cap myopathy (Cap myopathy) is a rare congenital myopathy characterized by subsarcolemmal “caps” and skeletal malformations. The slow‐twitch muscle tropomyosin 3, encoded by TPM3, regulates thin filament function; while TPM3 variants underlie nemaline myopathy and congenital fibre type disproportion, an association with cap myopathy has been established only recently.

Autosomal dominant TPM3 missense variants have been reported in six unrelated probands presenting with early‐onset muscle weakness, generalized hypotonia (HP:0001290), and skeletal features including micrognathia (HP:0000347), scoliosis (HP:0002650), high‐arched palate (HP:0000218), and respiratory insufficiency (HP:0002098). A 42-year-old man heterozygous for c.503G>A (p.Arg168His) was the first described case ([PMID:19553118]). A subsequent de novo c.502C>G (p.Arg168Gly) presentation confirmed the link ([PMID:24095155]). A three-generation pedigree with c.445C>A (p.Leu149Ile) included three affected members (two additional relatives) demonstrating segregation ([PMID:24239060]). Most recently, a novel c.709G>A (p.Glu237Lys) variant was identified in a 47-year-old man ([PMID:35688744]; total: 6 probands, 2 segregations).

Segregation analysis in the autosomal dominant family (c.445C>A) confirmed co-segregation in three generations with two additional affected relatives ([PMID:24239060]), consistent with dominant inheritance.

The cap myopathy variant spectrum in TPM3 is exclusively missense: c.502C>T (p.Arg168Cys), c.503G>A (p.Arg168His), c.445C>A (p.Leu149Ile), and c.709G>A (p.Glu237Lys), with p.Arg168His recurrent in unrelated cases.

Functional studies support a dominant-negative mechanism. In vitro muscle analyses of p.Arg168Cys showed ~50% mutant tropomyosin incorporation and reduced actin affinity, leading to impaired Ca2+-sensitive activation ([PMID:20554445]). Biochemical assays of Leu100Met, Ala156Thr, and Arg168His mutants demonstrated decreased tropomyosin–actin binding and reduced cooperativity of actomyosin interactions ([PMID:22749829]).

Integrating multiple independent probands (6), observed segregation, and concordant functional deficits, the TPM3–cap myopathy association is classified as Strong by ClinGen. Robust genetic and functional evidence supports clinical sequencing of TPM3 in cap myopathy. Key Take-home: Identification of pathogenic TPM3 missense variants informs precise diagnosis, genetic counseling, and management strategies.

References

• Neuromuscular Disorders • 2009 • A TPM3 mutation causing cap myopathy. PMID:19553118
• Neuromuscular Disorders • 2013 • Combined cap disease and nemaline myopathy in the same patient caused by an autosomal dominant mutation in the TPM3 gene. PMID:24095155
• Neuromuscular Disorders • 2014 • Novel TPM3 mutation in a family with cap myopathy and review of the literature. PMID:24239060
• Neuromuscular Disorders • 2022 • Novel autosomal dominant TPM3 mutation causes a combined congenital fibre type disproportion-cap disease histological pattern. PMID:35688744
• Neuromuscular Disorders • 2010 • Evidence for a dominant negative disease mechanism in cap myopathy due to TPM3. PMID:20554445
• Biochimica et Biophysica Acta • 2012 • Functional effects of congenital myopathy-related mutations in gamma-tropomyosin gene. PMID:22749829

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