title: Novel recessive myotilin mutation causes severe myofibrillar myopathy.
abstract: We identified the first homozygous and hence recessive mutation in the myotilin gene (MYOT) in a family affected by a severe myofibrillar myopathy (MFM). MFM is a rare, progressive and devastating disease of human skeletal muscle with distinct histopathological pattern of protein aggregates and myofibrillar degeneration. So far, only heterozygous missense mutations in MYOT have been associated with autosomal dominant myofibrillar myopathy, limb-girdle muscular dystrophy type 1A and distal myopathy. Myotilin itself is highly expressed in skeletal and cardiac muscle and is localized at the Z-disc and therefore interacts in sarcomere assembly. We performed whole-exome sequencing in a German family clinically diagnosed with MFM and identified a homozygous mutation in exon 2, c.16C > G (p.Arg6Gly). Using laser microdissection followed by quantitative mass spectrometry, we identified the myotilin protein as one component showing the highest increased abundance in the aggregates in the index patient. We suggest that the combined approach has a high potential as a new tool for the confirmation of unclassified variants which are found in whole-exome sequencing approaches.
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians University of Munich, Ziemssenstr. 1 A, 80336, Munich, Germany, jschessl@med.lmu.de.
authors.forename: Joachim
authors.initials: J
authors.lastname: Schessl
authors.forename: Elisa
authors.initials: E
authors.lastname: Bach
authors.forename: Simone
authors.initials: S
authors.lastname: Rost
authors.forename: Sarah
authors.initials: S
authors.lastname: Feldkirchner
authors.forename: Christiana
authors.initials: C
authors.lastname: Kubny
authors.forename: Stefan
authors.initials: S
authors.lastname: Müller
authors.forename: Franz-Georg
authors.initials: FG
authors.lastname: Hanisch
authors.forename: Wolfram
authors.initials: W
authors.lastname: Kress
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
mesh_terms: D000328:Adult; D064211:Connectin / Q000235:genetics*; D005091:Exons; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D008297:Male; D008840:Microfilament Proteins; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000175:diagnosis / Q000235:genetics
chemical_list: D064211:Connectin; C577290:MYOT protein, human; D008840:Microfilament Proteins