title: Abnormal actin binding of aberrant β-tropomyosins is a molecular cause of muscle weakness in TPM2-related nemaline and cap myopathy.
abstract: NM (nemaline myopathy) is a rare genetic muscle disorder defined on the basis of muscle weakness and the presence of structural abnormalities in the muscle fibres, i.e. nemaline bodies. The related disorder cap myopathy is defined by cap-like structures located peripherally in the muscle fibres. Both disorders may be caused by mutations in the TPM2 gene encoding β-Tm (tropomyosin). Tm controls muscle contraction by inhibiting actin-myosin interaction in a calcium-sensitive manner. In the present study, we have investigated the pathogenetic mechanisms underlying five disease-causing mutations in Tm. We show that four of the mutations cause changes in affinity for actin, which may cause muscle weakness in these patients, whereas two show defective Ca2+ activation of contractility. We have also mapped the amino acids altered by the mutation to regions important for actin binding and note that two of the mutations cause altered protein conformation, which could account for impaired actin affinity.
authors.affiliation: The Folkhälsan Institute of Genetics, Biomedicum Helsinki, Finland.
authors.forename: Minttu
authors.initials: M
authors.lastname: Marttila
authors.forename: Elina
authors.initials: E
authors.lastname: Lemola
authors.forename: William
authors.initials: W
authors.lastname: Wallefeld
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Memo
authors.forename: Kati
authors.initials: K
authors.lastname: Donner
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Laing
authors.forename: Steven
authors.initials: S
authors.lastname: Marston
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*; D000818:Animals; D006801:Humans; D017696:Myopathies, Nemaline / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020914:Myopathies, Structural, Congenital / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011994:Recombinant Proteins; D018411:Spodoptera; D014335:Tropomyosin / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000199:Actins; D011994:Recombinant Proteins; D014335:Tropomyosin