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Molecular pathology of myofibrillar myopathies

Published online by Cambridge University Press:  03 September 2008

Isidre Ferrer  and
Montse Olivé
Isidre Ferrer*
Affiliation:
Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Hospitalet de Llobregat, Spain. CIBERNED, Spain.
Montse Olivé
Affiliation:
Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Hospitalet de Llobregat, Spain. CIBERNED, Spain.
*
*Corresponding author: Isidre Ferrer, Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, carrer Feixa Llarga sn, 08907 Hospitalet de Llobregat, Spain. Tel: +34 932607452; Fax: +34 932607503; E-mail: [email protected]
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Abstract

Myofibrillar myopathies (MFMs) are clinically and genetically heterogeneous muscle disorders that are defined morphologically by the presence of foci of myofibril dissolution, accumulation of myofibrillar degradation products, and ectopic expression of multiple proteins. MFMs are the paradigm of conformational protein diseases of the skeletal (and cardiac) muscles characterised by intracellular protein accumulation in muscle cells. Understanding of this group of disorders has advanced in recent years through the identification of causative mutations in various genes, most of which encode proteins of the sarcomeric Z-disc, including desmin, αB-crystallin, myotilin, ZASP and filamin C. This review focuses on the MFMs arising from defects in these proteins, summarising genetic and clinical features of the disorders and then discussing emerging understanding of the molecular pathogenic mechanisms leading to muscle fibre degeneration. Defective extralysosomal degradation of proteins is now recognised as an important element in this process. Several factors – including mutant proteins, a defective ubiquitin–proteasome system, aggresome formation, mutant ubiquitin, p62, oxidative stress and abnormal regulation of some transcription factors – are thought to participate in the cascade of events occurring in muscle fibres in MFMs.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 10 , October 2008 , e25
Copyright
Copyright © Cambridge University Press 2008

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References

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Further reading, resources and contacts

The entry for myofibrillar myopathies on the GENEreviews website, by D. Selcen and A.G. Engel, covers clinical and pathological aspects of these diseases; it also provides information on genetic testing and its use in diagnosis, management and genetic counselling of individuals and families with MFMs:

http://www.genereviews.orgGoogle Scholar
http://neuromuscular.wustl.eduGoogle Scholar