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

Eugenio Maria Mercuri, Enrico Silvio Bertini, Minttu Marttila, Vilma-Lotta Lehtokari, Steven Marston, Tuula A. Nyman, Christine Barnerias, Alan H. Beggs, Enrico Bertini, Özge Ceyhan-Birsoy, Pascal Cintas, Marion Gerard, Brigitte Gilbert-Dussardier, Jacob S. Hogue, Cheryl Longman, Bruno Eymard, Moshe Frydman, Peter B. Kang, Lars Klinge, Hanna KolskiHans Lochmüller, Laurent Magy, Véronique Manel, Michèle Mayer, Kathryn N. North, Sylviane Peudenier-Robert, Helena Pihko, Frank J. Probst, Ricardo Reisin, Willie Stewart, Ana Lia Taratuto, Marianne De Visser, Ekkehard Wilichowski, John Winer, Kristen Nowak, Nigel G. Laing, Tom L. Winder, Nicole Monnier, Nigel F. Clarke, Katarina Pelin, Mikaela Grönholm, Carina Wallgren-Pettersson

Risultato della ricerca: Contributo in rivistaArticolo in rivista

62 Citazioni (Scopus)

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 Ca(2+) 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.
Lingua originaleEnglish
pagine (da-a)779-790
Numero di pagine12
RivistaHuman Mutation
Volume35
DOI
Stato di pubblicazionePubblicato - 2014

Keywords

  • Actins
  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Child
  • Child, Preschool
  • Databases, Genetic
  • Female
  • Genetic Association Studies
  • Humans
  • Infant
  • Male
  • Molecular Sequence Data
  • Muscle, Skeletal
  • Muscular Diseases
  • Mutation
  • Phenotype
  • Phosphorylation
  • Protein Binding
  • Sequence Alignment
  • TPM2
  • TPM3
  • Tropomyosin
  • Young Adult
  • actin
  • congenital myopathy
  • genotype-phenotype correlation
  • hypercontractile phenotype

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