title: Titin mutations as the molecular basis for dilated cardiomyopathy.
abstract: Dilated cardiomyopathy (DCM) is a heterogeneous cardiac disease characterized by ventricular dilatation and systolic dysfunction. Recent genetic studies have revealed that mutations in genes for cardiac sarcomere components lead to DCM. The cardiac sarcomere consists of thick and thin filaments and a giant protein, titin. Because one of the loci of familial DCM was mapped to the region of the titin gene, we searched for titin mutations in the patients and identified four possible disease-associated mutations. Two mutations, Val54Met and Ala743Val, were found in the Z-line region of titin and decreased binding affinities of titin to Z-line proteins T-cap/telethonin and alpha-actinin, respectively, in yeast two-hybrid assays. The other two mutations were found in the cardiac-specific N2-B region of titin and one of them was a nonsense mutation, Glu4053ter, presumably encoding for a truncated nonfunctional molecule. These observations suggest that titin mutations may cause DCM in a subset of the patients.
authors.affiliation: Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Manatsu
authors.initials: M
authors.lastname: Itoh-Satoh
authors.forename: Takeharu
authors.initials: T
authors.lastname: Hayashi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nishi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Koga
authors.forename: Takuro
authors.initials: T
authors.lastname: Arimura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Koyanagi
authors.forename: Megumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hohda
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ueda
authors.forename: Tatsuhito
authors.initials: T
authors.lastname: Nouchi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Hiroe
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Marumo
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Imaizumi
authors.forename: Michio
authors.initials: M
authors.lastname: Yasunami
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
mesh_terms: D000185:Actinin / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism; D002645:Chickens; D064211:Connectin; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011817:Rabbits; D012518:Sarcomeres / Q000378:metabolism; D016415:Sequence Alignment; D020798:Two-Hybrid System Techniques
chemical_list: D064211:Connectin; D009124:Muscle Proteins; C577292:TCAP protein, human; C577285:TTN protein, human; D000185:Actinin; D011494:Protein Kinases