Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies.

Mutations affecting skeletal muscle isoforms of the tropomyosingenes 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 TPM2and TPM3 genes. Included are altogether 93 families: 53 with TPM2mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2and 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 TPM2mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2group. Previous studies have shown that five of the mutations in TPM2and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contracturesof 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 contracturesthan the hypercontractile group (7/ 19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosinhead-to-tail binding.