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

Marttila, M. et al. (2014) Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies. Human Mutation, 35(7), pp. 779-790. (doi: 10.1002/humu.22554) (PMID:24692096) (PMCID:PMC4200603)

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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 ( 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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Stewart, Dr William
Authors: Marttila, M., Lehtokari, V.-L., Marston, S., Nyman, T. A., Barnerias, C., Beggs, A. H., Bertini, E., Ceyhan-Birsoy, Ö., Cintas, P., Gerard, M., Gilbert-Dussardier, B., Hogue, J. S., Longman, C., Eymard, B., Frydman, M., Kang, P. B., Klinge, L., Kolski, H., Lochmüller, H., Magy, L., Manel, V., Mayer, M., Mercuri, E., North, K. N., Peudenier-Robert, S., Pihko, H., Probst, F. J., Reisin, R., Stewart, W., Taratuto, A. L., de Visser, M., Wilichowski, E., Winer, J., Nowak, K., Laing, N. G., Winder, T. L., Monnier, N., Clarke, N. F., Pelin, K., Grönholm, M., and Wallgren-Pettersson, C.
College/School:College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:Human Mutation
ISSN (Online):1098-1004
Published Online:01 April 2014
Copyright Holders:Copyright © 2014 Wiley Periodicals, Inc.
First Published:First published in Human Mutation 35(7): 779-790
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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