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Mutation Update and Genotype-Phenotype Correlations of Novel and Previously Described Mutations in TPM2 and TPM3 Causing Congenital Myopathies

Lookup NU author(s): Dr Lars Klinge, Professor Hanns Lochmuller


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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.

Publication metadata

Author(s): Marttila M, Lehtokari VL, Marston S, Nyman TA, Barnerias C, Beggs AH, Bertini E, Ceyhan-Birsoy O, Cintas P, Gerard M, Gilbert-Dussardier B, Hogue JS, Longman C, Eymard B, Frydman M, Kang PB, Klinge L, Kolski H, Lochmuller H, Magy L, Manel V, Mayer M, Mercuri E, North KN, Peudenier-Robert S, Pihko H, Probst FJ, Reisin R, Stewart W, Taratuto AL, de Visser M, Wilichowski E, Winer J, Nowak K, Laing NG, Winder TL, Monnier N, Clarke NF, Pelin K, Gronholm M, Wallgren-Pettersson C

Publication type: Article

Publication status: Published

Journal: Human Mutation

Year: 2014

Volume: 35

Issue: 7

Pages: 779-790

Print publication date: 01/07/2014

Online publication date: 01/05/2014

Acceptance date: 17/03/2014

ISSN (print): 1059-7794

ISSN (electronic): 1098-1004

Publisher: Wiley-Blackwell Publishing Ltd.


DOI: 10.1002/humu.22554

PubMed id: 24692096


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Funder referenceFunder name
British Heart Foundation
Finska Lakaresallskapet
Medicinska understodsforeningen Liv och Halsa r.f.
Academy of Finland
Association Francaise contre les Myopathies
Foundation for Building Strength for Nemaline Myopathy
Ricerca Finalizzata Ministry of Health
Sigrid Juselius Foundation
305121European Union
305444European Union
APP1022707Australian National Health, Medical Research Council (NHMRC)
APP1026933NHMRC of Australia
APP1031893NHMRC Centre of Research Excellence
APP1035828NHMRC of Australia
MDA201302Muscular Dystrophy Association
R01 AR044345National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH