Submission Details

TPM3 was first reported in relation to autosomal dominant TPM3-related myopathy in 1995 (Laing et al., PMID: 7704029), with the first autosomal recessive case reported in 1999 (Tan et al., PMID: 10619715). Cases of TPM3-related Myopathy have historically been categorized by histological features in muscle biopsy and include nemaline myoapthy, cap myoapthy, and myopathy with fiber-type disproportion on a spectrum of severity. Over twenty-five unique variants (e.g. missense, nonsense, in-frame indel, etc) have been reported in humans, mostly consisting of gain-of-function or dominant negative missense variants in the AD form and loss-of-function null variants in the AR form. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 13 probands in six publications (PMIDs: 7704029, 10619715, 18300303, 26418456, 20554445, 31866162). These probands display various phenotypes, with the majority showing hypotonia, delayed motor milestones, muscle weakness, and Type 1 muscle fiber hypotrophy. Variants in this gene segregated with disease in 15 additional family members in two families with the maximum segregation evidence awarded. Significantly more evidence for both the dominant and recessive forms is available in the literature, but the maximum score for genetic evidence has been reached. In the autosomal dominant form of TPM3-related myopathy, the mechanism for disease is different for individual variants. The majority of variants cause a dominant negative effect where the inclusion of mutant TPM3 leads to reduced calcium sensitivity and subsequent reduced contractile ability known as the "hypocontractile" form characterized by early-onset muscular hypotonia and weakness. Some variants, however, cause a heterozygous gain of function which leads to increased calcium sensitivity and subsequent increased contractile ability known as the "hypercontractile" form characterized by early-onset muscle stiffness with other symptoms onset usually occuring later in life. (Marttila et al 2014, PMID: 24692096) The autosomal recessive form usually results from loss-of-function null variants that cannot incorporate themselves into the appropriate configurations due to head-tail polymerization, however a recent case has demonstrated a recessive case resulting from a missense variant (Tan et al., PMID: 10619715). This gene-disease association is additionally supported by TPM3's biochemical function, unique expression in the skeletal muscle tissue, physical protein interaction with ACTA1, altered function of TPM3 mutant proteins decreasing the affinity for actin and modifying the calcium response, and a knock-in mouse model of the well-characterized TPM3 variant Met9Arg that recapitulates much of the human disorder. In summary, TPM3 is definitively associated with semidominant TPM3-related myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time