Journal article
Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies
Brain (London, England : 1878), Vol.136(2), pp.508-521
02/2013
DOI: 10.1093/brain/aws344
PMCID: PMC3572924
PMID: 23413262
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.
Details
- Title: Subtitle
- Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies
- Creators
- Ann E Davidson - 1 Department of Paediatrics, University of Michigan Medical Centre, Ann Arbor, MI 48109-2200, USAFazeel M Siddiqui - 2 Department of Neurology, Southern Illinois University School of Medicine, Springfield, IL 62794, USAMichael A Lopez - 1 Department of Paediatrics, University of Michigan Medical Centre, Ann Arbor, MI 48109-2200, USAPeter Lunt - 3 Department of Clinical Genetics, University Hospitals Bristol NHS Trust, Bristol, BS1 3NU, UKHeather A Carlson - 4 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USABrian E Moore - 5 Department of Pathology, Southern Illinois University School of Medicine, Springfield, IL 62794, USASeth Love - 6 Department of Neuropathology, University of Bristol, Frenchay Hospital, Bristol BS16 1LE, UKDonald E Born - 7 Department of Pathology (Neuropathology), University of Washington, Seattle, WA 98195, USAHelen Roper - 8 Department of Paediatric Neurology, Birmingham Heartlands Hospital, Birmingham B9 5SS, UKAnirban Majumdar - 9 Department of Paediatric Neurology, Frenchay Hospital, Bristol BS16 1LE, UKSuman Jayadev - 10 Department of Neurology, University of Washington, Seattle, WA 98195, USAHunter R Underhill - 11 Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USACorrine O Smith - 10 Department of Neurology, University of Washington, Seattle, WA 98195, USAMaja von der Hagen - 12 Department of Paediatrics, Children’s Hospital, Technical University, Pathology, Fetscherstrasse 74, Dresden 01307, GermanyAngela Hubner - 12 Department of Paediatrics, Children’s Hospital, Technical University, Pathology, Fetscherstrasse 74, Dresden 01307, GermanyPhilip Jardine - 13 Department of Paediatric Neurology, Bristol Royal Hospital for Children, Bristol BS28BJ, UKAndria Merrison - 14 Department of Neurology, Frenchay Hospital, Bristol BS16 1LE, UKElizabeth Curtis - 15 Department of Pathology, University Hospital, Birmingham B9 5SS, UKThomas Cullup - 16 Diagnostics Genetics Laboratory, GSTS Pathology, Guy’s Hospital, London SE1 9RT, UKHeinz Jungbluth - 17 Department of Paediatric Neurology, Neuromuscular Service, Evelina Children’s Hospital, St Thomas’ Hospital, London SE1 7EH, UKMary O Cox - 18 Department of Pathology, The University of Iowa, Iowa City, IA 52242, USAThomas L Winder - 19 PreventionGenetics, Marshfield, WI 54449, USAHossam Abdel Salam - 2 Department of Neurology, Southern Illinois University School of Medicine, Springfield, IL 62794, USAJun Z Li - 20 Department of Human Genetics, University of Michigan Medical Centre, Ann Arbor, MI 48109-2200, USASteven A Moore - 18 Department of Pathology, The University of Iowa, Iowa City, IA 52242, USAJames J Dowling - 1 Department of Paediatrics, University of Michigan Medical Centre, Ann Arbor, MI 48109-2200, USA
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.136(2), pp.508-521
- Publisher
- Oxford University Press
- DOI
- 10.1093/brain/aws344
- PMID
- 23413262
- PMCID
- PMC3572924
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Language
- English
- Date published
- 02/2013
- Academic Unit
- Pathology
- Record Identifier
- 9984047730202771
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