title: Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing 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 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.
authors.affiliation: The Folkhälsan Institute of Genetics and the Department of Medical Genetics, University of Helsinki, Haartman Institute, Biomedicum Helsinki, Finland.
authors.forename: Minttu
authors.initials: M
authors.lastname: Marttila
authors.forename: Vilma-Lotta
authors.initials: VL
authors.lastname: Lehtokari
authors.forename: Steven
authors.initials: S
authors.lastname: Marston
authors.forename: Tuula A
authors.initials: TA
authors.lastname: Nyman
authors.forename: Christine
authors.initials: C
authors.lastname: Barnerias
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Ozge
authors.initials: O
authors.lastname: Ceyhan-Birsoy
authors.forename: Pascal
authors.initials: P
authors.lastname: Cintas
authors.forename: Marion
authors.initials: M
authors.lastname: Gerard
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gilbert-Dussardier
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Hogue
authors.forename: Cheryl
authors.initials: C
authors.lastname: Longman
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.forename: Moshe
authors.initials: M
authors.lastname: Frydman
authors.forename: Peter B
authors.initials: PB
authors.lastname: Kang
authors.forename: Lars
authors.initials: L
authors.lastname: Klinge
authors.forename: Hanna
authors.initials: H
authors.lastname: Kolski
authors.forename: Hans
authors.initials: H
authors.lastname: Lochmüller
authors.forename: Laurent
authors.initials: L
authors.lastname: Magy
authors.forename: Véronique
authors.initials: V
authors.lastname: Manel
authors.forename: Michèle
authors.initials: M
authors.lastname: Mayer
authors.forename: Eugenio
authors.initials: E
authors.lastname: Mercuri
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
authors.forename: Sylviane
authors.initials: S
authors.lastname: Peudenier-Robert
authors.forename: Helena
authors.initials: H
authors.lastname: Pihko
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Probst
authors.forename: Ricardo
authors.initials: R
authors.lastname: Reisin
authors.forename: Willie
authors.initials: W
authors.lastname: Stewart
authors.forename: Ana Lia
authors.initials: AL
authors.lastname: Taratuto
authors.forename: Marianne
authors.initials: M
authors.lastname: de Visser
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Wilichowski
authors.forename: John
authors.initials: J
authors.lastname: Winer
authors.forename: Kristen
authors.initials: K
authors.lastname: Nowak
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Laing
authors.forename: Tom L
authors.initials: TL
authors.lastname: Winder
authors.forename: Nicole
authors.initials: N
authors.lastname: Monnier
authors.forename: Nigel F
authors.initials: NF
authors.lastname: Clarke
authors.forename: Katarina
authors.initials: K
authors.lastname: Pelin
authors.forename: Mikaela
authors.initials: M
authors.lastname: Grönholm
authors.forename: Carina
authors.initials: C
authors.lastname: Wallgren-Pettersson
mesh_terms: D000199:Actins / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D030541:Databases, Genetic; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D016415:Sequence Alignment; D014335:Tropomyosin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000199:Actins; C518659:TPM2 protein, human; C498783:TPM3 protein, human; D014335:Tropomyosin
keywords: TPM2; TPM3; actin; congenital myopathy; genotype-phenotype correlation; hypercontractile phenotype