Hereditary myopathy with early respiratory failure is associated with misfolding of the titin fibronectin III 119 subdomain

Carola Hedberg; Alejandro Gomez Toledo; Claes M Gustafsson; Göran Larson; Anders Oldfors; Bertil Macao

doi:10.1016/j.nmd.2014.02.003

Hereditary myopathy with early respiratory failure is associated with misfolding of the titin fibronectin III 119 subdomain

Neuromuscul Disord. 2014 May;24(5):373-9. doi: 10.1016/j.nmd.2014.02.003. Epub 2014 Feb 15.

Authors

Carola Hedberg¹, Alejandro Gomez Toledo², Claes M Gustafsson³, Göran Larson², Anders Oldfors⁴, Bertil Macao³

Affiliations

¹ Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden. Electronic address: carola.hedberg@gu.se.
² Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
³ Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
⁴ Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.

PMID: 24636144
DOI: 10.1016/j.nmd.2014.02.003

Abstract

Hereditary myopathy with early respiratory failure is a rare disease with muscle weakness and respiratory failure as early symptoms. Muscle pathology is characterized by the presence of multiple cytoplasmic bodies and other protein aggregates in muscle fibers. The disease is associated with mutations in the titin gene (TTN). All patients harbor mutations located in exon 343 in the TTN gene that codes for the fibronectin III domain 119 (FN3 119) in the 10th motif of the 11-element motif A-band super-repeat. We investigated how such disease-causing mutations affect the biochemical behavior of this titin domain. All five disease-causing amino acid changes analyzed by us (p.P30068R, p.C30071R, p.W30088R, p.W30088C and p.P30091L) resulted in impaired FN3 119 domain solubility. In contrast, amino acid changes associated with common SNPs (p.V30076I, p.R30107C and p.S30125F) did not have this effect. In silico analyses further support the notion that disease-causing mutations impair proper folding of the FN3 119 domain. The results suggest that hereditary myopathy with early respiratory failure is caused by defective protein folding.

Keywords: HMERF; Mutation; Myopathy; Protein aggregates; Titin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Connectin / chemistry*
Connectin / genetics*
Databases, Genetic
Exons
Fibronectins / chemistry
Fibronectins / genetics*
Genetic Diseases, Inborn / genetics*
Genetic Diseases, Inborn / metabolism*
Humans
Models, Molecular
Muscular Diseases / genetics*
Muscular Diseases / metabolism*
Mutation*
Protein Aggregates
Protein Folding
Protein Interaction Domains and Motifs
Respiratory Insufficiency / genetics*
Respiratory Insufficiency / metabolism*
Solubility

Substances

Connectin
Fibronectins
Protein Aggregates
TTN protein, human
fibronectin type III like peptide, human

Supplementary concepts

Hereditary Myopathy with Early Respiratory Failure