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: Ann E Davidson, Fazeel M Siddiqui, Michael A Lopez, Peter Lunt, Heather A Carlson, Brian E Moore, Seth Love, Donald E Born, Helen Roper, Anirban Majumdar, Suman Jayadev, Hunter R Underhill, Corrine O Smith, Maja von der Hagen, Angela Hubner, Philip Jardine, Andria Merrison, Elizabeth Curtis, Thomas Cullup, Heinz Jungbluth, Mary O Cox, Thomas L Winder, Hossam Abdel Salam, Jun Z Li, Steven A Moore, James J Dowling
• Journal: Brain : a journal of neurology (Brain) Vol. 136 Issue Pt 2 Pg. 508-21 (Feb 2013) ISSN: 1460-2156 [Electronic] England
• PMID: 23413262 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• TPM2 protein, human
• Tropomyosin
• Lysine

Topics

• Adolescent
• Adult
• Amino Acid Sequence
• Animals
• Child
• Female
• Humans
• Lysine (genetics)
• Male
• Middle Aged
• Molecular Sequence Data
• Muscular Diseases (diagnosis, genetics, pathology)
• Sequence Deletion
• Tropomyosin (chemistry, genetics)
• Young Adult
• Zebrafish