Mutation Update and Genotype-Phenotype Correlations of Novel and Previously Described Mutations inTPM2andTPM3Causing Congenital Myopathies

Abstract

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosin head-to-tail binding.

TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype

“…Six TPM2 and one TPM3 mutation that result in increased Ca 2+ -sensitivity have been reported in patients with only moderately progressive contractures and myopathic weakness. 11,12,33 In contrast, our patients present with a distinctive and considerably more severe congenital hypercontractile phenotype with generalized muscle stiffness leading to severe respiratory failure in the neonatal period in one case, which represents a novel phenotype for tropomyosin-related disease.…”

Tropomyosin – master regulator of actin filament function in the cytoskeleton

“…On the basis of the above studies, it is to be expected that genetic manipulation of Tpms will reveal specific roles for the different Tpm isoforms in many, if not most, physiological processes owing to their ability to uniquely define the functional characteristics of the actin filaments that are engaged in specific processes. It is surprising, however, that no mutations in human cytoskeletal Tpms have been associated with disease, whereas many mutations in muscle Tpms are associated with muscle conditions (Marttila et al, 2014). The development of drugs that target specific Tpm isoforms might open the door to a range of therapeutic opportunities, such as the treatment of cancer (Stehn et al, 2013).…”

Noncanonical roles for Tropomyosin during myogenesis

“…The human genome encodes four Tropomyosin isoforms (TPM1-4), and congenital myopathies have been associated with dominant Tropomyosin mutations (Marttila et al, 2014;Olson et al, 2001). Tropomyosin is a coiled-coil protein comprised of seven pseudo-repeat domains, and each domain contains an α-zone that interacts with F-actin when muscle is relaxed (Marttila et al, 2014).…”

“…Tropomyosin alleles are associated with myopathies Dominant mutations in TPM1, TPM2, and TPM3 are associated with congenital myopathies (Marttila et al, 2014) and cardiomyopathies (Karibe et al, 2001;Olson et al, 2001). The TPM1 E54K allele was identified in patients with dilated cardiomyopathy and in vitro thin filament reconstitution experiments show the E54K protein overinhibits actomyosin interactions, which decreases force generation during systolic contraction (Bai et al, 2012).…”

“…7D-F), which argues that Tm2-mediated actomyosin contractions are indeed required for myotube elongation. A second TPM1 allele, E40K, also interrupts actomysosin contractions (Bai et al, 2012), and TPM2 E41K is associated with congenital myopathies (Marttila et al, 2014). This raises the possibility that myotube elongation is affected in patients with TPM2-associated congenital myopathies.…”