title: Hereditary myopathy with early respiratory failure is associated with misfolding of the titin fibronectin III 119 subdomain.
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.
authors.affiliation: Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden. Electronic address: carola.hedberg@gu.se.
authors.forename: Carola
authors.initials: C
authors.lastname: Hedberg
authors.affiliation: Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Alejandro Gomez
authors.initials: AG
authors.lastname: Toledo
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Claes M
authors.initials: CM
authors.lastname: Gustafsson
authors.affiliation: Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Larson
authors.affiliation: Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Oldfors
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Bertil
authors.initials: B
authors.lastname: Macao
mesh_terms: D000595:Amino Acid Sequence; D064211:Connectin / Q000737:chemistry* / Q000235:genetics*; D030541:Databases, Genetic; D005091:Exons; D005353:Fibronectins / Q000737:chemistry / Q000235:genetics*; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D066329:Protein Aggregates; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D012131:Respiratory Insufficiency / Q000235:genetics* / Q000378:metabolism*; D012995:Solubility
chemical_list: D064211:Connectin; D005353:Fibronectins; D066329:Protein Aggregates; C577285:TTN protein, human; C501364:fibronectin type III like peptide, human
keywords: HMERF; Mutation; Myopathy; Protein aggregates; Titin