title: Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin.
abstract: Tibial muscular dystrophy (TMD) is an autosomal dominant late-onset distal myopathy linked to chromosome 2q31. The linked region includes the giant TTN gene, which encodes the central sarcomeric protein, titin. We have previously shown a secondary calpain-3 defect to be associated with TMD, which further underscored that titin is the candidate. We now report the first mutations in TTN to cause a human skeletal-muscle disease, TMD. In Mex6, the last exon of TTN, a unique 11-bp deletion/insertion mutation, changing four amino acid residues, completely cosegregated with all tested 81 Finnish patients with TMD in 12 unrelated families. The mutation was not found in 216 Finnish control samples. In a French family with TMD, a Leu-->Pro mutation at position 293,357 in Mex6 was discovered. Mex6 is adjacent to the known calpain-3 binding site Mex5 of M-line titin. Immunohistochemical analysis using two exon-specific antibodies directed to the M-line region of titin demonstrated the specific loss of carboxy-terminal titin epitopes in the TMD muscle samples that we studied, thus implicating a functional defect of the M-line titin in the genesis of the TMD disease phenotype.
authors.affiliation: Department of Medical Genetics and The Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland.
authors.forename: Peter
authors.initials: P
authors.lastname: Hackman
authors.forename: Anna
authors.initials: A
authors.lastname: Vihola
authors.forename: Henna
authors.initials: H
authors.lastname: Haravuori
authors.forename: Sylvie
authors.initials: S
authors.lastname: Marchand
authors.forename: Jaakko
authors.initials: J
authors.lastname: Sarparanta
authors.forename: Jerome
authors.initials: J
authors.lastname: De Seze
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
authors.forename: Christian
authors.initials: C
authors.lastname: Witt
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Isabelle
authors.initials: I
authors.lastname: Richard
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D064211:Connectin; D004252:DNA Mutational Analysis; D000939:Epitopes / Q000032:analysis; D005091:Exons / Q000235:genetics; D005387:Finland; D005602:France; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D011485:Protein Binding; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D064211:Connectin; D000939:Epitopes; D009124:Muscle Proteins; C577285:TTN protein, human; D011494:Protein Kinases