title: Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies.
abstract: The β-tropomyosin gene encodes a component of the sarcomeric thin filament. Rod-shaped dimers of tropomyosin regulate actin-myosin interactions and β-tropomyosin mutations have been associated with nemaline myopathy, cap myopathy, Escobar syndrome and distal arthrogryposis types 1A and 2B. In this study, we expand the allelic spectrum of β-tropomyosin-related myopathies through the identification of a novel β-tropomyosin mutation in two clinical contexts not previously associated with β-tropomyosin. The first clinical phenotype is core-rod myopathy, with a β-tropomyosin mutation uncovered by whole exome sequencing in a family with autosomal dominant distal myopathy and muscle biopsy features of both minicores and nemaline rods. The second phenotype, observed in four unrelated families, is autosomal dominant trismus-pseudocamptodactyly syndrome (distal arthrogryposis type 7; previously associated exclusively with myosin heavy chain 8 mutations). In all four families, the mutation identified was a novel 3-bp in-frame deletion (c.20_22del) that results in deletion of a conserved lysine at the seventh amino acid position (p.K7del). This is the first mutation identified in the extreme N-terminus of β-tropomyosin. To understand the potential pathogenic mechanism(s) underlying this mutation, we performed both computational analysis and in vivo modelling. Our theoretical model predicts that the mutation disrupts the N-terminus of the α-helices of dimeric β-tropomyosin, a change predicted to alter protein-protein binding between β-tropomyosin and other molecules and to disturb head-to-tail polymerization of β-tropomyosin dimers. To create an in vivo model, we expressed wild-type or p.K7del β-tropomyosin in the developing zebrafish. p.K7del β-tropomyosin fails to localize properly within the thin filament compartment and its expression alters sarcomere length, suggesting that the mutation interferes with head-to-tail β-tropomyosin polymerization and with overall sarcomeric structure. We describe a novel β-tropomyosin mutation, two clinical-histopathological phenotypes not previously associated with β-tropomyosin and pathogenic data from the first animal model of β-tropomyosin-related myopathies.
authors: Department of Paediatrics, University of Michigan Medical Centre, Ann Arbor, MI 48109-2200, USA.
authors: Ann E
authors: AE
authors: Davidson
authors: Fazeel M
authors: FM
authors: Siddiqui
authors: Michael A
authors: MA
authors: Lopez
authors: Peter
authors: P
authors: Lunt
authors: Heather A
authors: HA
authors: Carlson
authors: Brian E
authors: BE
authors: Moore
authors: Seth
authors: S
authors: Love
authors: Donald E
authors: DE
authors: Born
authors: Helen
authors: H
authors: Roper
authors: Anirban
authors: A
authors: Majumdar
authors: Suman
authors: S
authors: Jayadev
authors: Hunter R
authors: HR
authors: Underhill
authors: Corrine O
authors: CO
authors: Smith
authors: Maja
authors: M
authors: von der Hagen
authors: Angela
authors: A
authors: Hubner
authors: Philip
authors: P
authors: Jardine
authors: Andria
authors: A
authors: Merrison
authors: Elizabeth
authors: E
authors: Curtis
authors: Thomas
authors: T
authors: Cullup
authors: Heinz
authors: H
authors: Jungbluth
authors: Mary O
authors: MO
authors: Cox
authors: Thomas L
authors: TL
authors: Winder
authors: Hossam
authors: H
authors: Abdel Salam
authors: Jun Z
authors: JZ
authors: Li
authors: Steven A
authors: SA
authors: Moore
authors: James J
authors: JJ
authors: Dowling
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D005260:Female; D006801:Humans; D008239:Lysine / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion; D014335:Tropomyosin / Q000737:chemistry / Q000235:genetics*; D055815:Young Adult; D015027:Zebrafish
chemical_list: C518659:TPM2 protein, human; D014335:Tropomyosin; D008239:Lysine