Molecular Genetics of Myopathies Caused by β‐Tropomyosin Mutations

Abstract

Mutations in the gene encoding β‐tropomyosin, TPM2, cause clinically and histologically overlapping congenital myopathies such as nemaline myopathy, cap myopathy and core‐rod myopathy, and often also a fibre size disproportion between type 1 and type 2 muscle fibres. In addition, TPM2 mutations can cause distal arthrogryposis and Escobar syndrome, or unspecific myopathies with various combinations of clinical and histological features. The vast majority of the TPM2 mutations are dominant, either de novo or familial. Missense mutations and in‐frame deletions or insertions of single amino acids are the most common types of mutation. Three dominant donor splice site mutations have also been described, predicted to cause exon skipping and subsequent loss of 42 amino acids. Only one recessive mutation has been identified in TPM2, that is, a nonsense mutation causing nemaline myopathy with Escobar syndrome. Of the 30 different TPM2 mutations identified to date, six are gain‐of‐function mutations causing increased muscle contractility.

Key Concepts:

  • Dominant mutations in the TPM2 gene cause a variety of congenital myopathies and distal arthrogryposis.

  • Recessive mutations in TPM2 are rare.

  • Tropomyosin mutations alter actin‐tropomyosin interactions, tropomyosin dimer formation and muscle contraction.

  • Gain‐of‐function mutations cause increased muscle contractility.

  • Hypercontractile molecular phenotypes result in distal arthrogryposis and congenital myopathies with contractures.

Keywords: tropomyosin; mutation; nemaline myopathy; cap myopathy; distal arthrogryposis; congenital fibre‐type disproportion; core‐rod myopathy; Escobar syndrome; skeletal muscle

Figure 1.

Schematic presentation of the β‐tropomyosin dimer with disease‐causing mutations. α‐Zones are shown in purple and the tropomyosin‐overlapping regions are separated by lines in the N‐ and C‐terminal ends of the molecules. The mutations increasing Ca2+‐sensitivity are in green, while those decreasing it are in black. The mutation hotspot Arg133 and the recurrent mutations p.Lys7del and p.Glu139del are indicated by black arrows below the sequence. The figure was created using the PyMol software (http://www.pymol.org) and the Protein Databank structure 1C1GA.

Figure 2.

On‐state actin‐tropomyosin contacts and disease mutations. The β‐tropomyosin sequence is divided into the α‐ and β‐zones. Amino acids interacting with actin are shown in purple and orange. The TPM2 mutations are written above the sequence. The mutations increasing Ca2+‐sensitivity are shown in green, while those decreasing it are shown in black. The tropomyosin‐overlapping regions are framed by light blue boxes at the N‐ and C‐terminal of the sequence.

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Further Reading

Jungbluth H and Wallgren‐Pettersson C (2014) The congenital (structural) myopathies. In: Rimoin DL, Connor JM, Pyeritz RE and Korf BR (eds) Emery & Rimoin's Principles and Practice of Medical Genetics, 6th edn, chap. 127, pp. 1–51. London: Churchill Livingstone.

Nowak K, Davis MR, Wallgren‐Pettersson C, Lamont PJ and Laing NG (2012) Clinical utility gene card for nemaline myopathy. European Journal of Human Genetics 20 (6).

Wallgren‐Pettersson C and Goebel HH (2009) Nemaline Myopathies. In: Lang F (ed.) Encyclopedia of Molecular Mechanisms of Disease, pp. 1439–1440. Berlin: Springer.

Wallgren‐Pettersson C, Kalimo H and Lammens M (2013) Nebulin: nemaline myopathies and associated disorders. In: Goebel HG, Sewry CA and Weller RO (eds) Muscle Disease: Pathology and Genetics, 2nd edn, pp. 152–156. Hoboken, NJ: Wiley‐Blackwell. ISBN: 978‐0‐470–67205‐1

Wallgren‐Pettersson C and Laing NG (2010) The congenital myopathies. In: Karpati G, Hilton‐Jones D, Griggs RC and Bushby K (eds) Disorders of Voluntary Muscle, 8th edn, pp. 282–298. Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, Sao Paulo, Delhi, Dubai, Tokyo: Cambridge University Press.

Wallgren‐Pettersson C, Sewry CA, Nowak KJ and Laing NG (2011) Nemaline myopathies. Seminars in Pediatric Neurology 18 (4): 230–238.

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Pelin, Katarina, Marttila, Minttu, and Wallgren‐Pettersson, Carina(Oct 2014) Molecular Genetics of Myopathies Caused by β‐Tropomyosin Mutations. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025299]