title: Structural analysis of obscurin gene in hypertrophic cardiomyopathy.
abstract: Hypertrophic cardiomyopathy (HCM) is a cardiac disease characterized by left ventricular hypertrophy with diastolic dysfunction. Molecular genetic studies have revealed that HCM is caused by mutations in genes for sarcomere/Z-band components including titin/connectin and its associate proteins. However, disease-causing mutations can be found in about half of the patients, suggesting that other disease-causing genes remain to be identified. To explore a novel disease gene, we searched for obscurin gene (OBSCN) mutations in HCM patients, because obscurin interacts with titin/connectin. Two linked variants, Arg4344Gln and Ala4484Thr, were identified in a patient and functional analyses demonstrated that Arg4344Gln affected binding of obscurin to Z9-Z10 domains of titin/connectin, whereas Ala4484Thr did not. Myc-tagged obscurin showed that Arg4344Gln impaired obscurin localization to Z-band. These observations suggest that the obscurin abnormality may be involved in the pathogenesis of HCM.
authors: Department of Molecular Pathogenesis, Medical Research Institute and Laboratory of Genome Diversity, School of Biomedical Science, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors: Takuro
authors: T
authors: Arimura
authors: Yuji
authors: Y
authors: Matsumoto
authors: Osamu
authors: O
authors: Okazaki
authors: Takeharu
authors: T
authors: Hayashi
authors: Megumi
authors: M
authors: Takahashi
authors: Natsuko
authors: N
authors: Inagaki
authors: Kunihiko
authors: K
authors: Hinohara
authors: Naoto
authors: N
authors: Ashizawa
authors: Keisuke
authors: K
authors: Yano
authors: Akinori
authors: A
authors: Kimura
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D064067:Rho Guanine Nucleotide Exchange Factors; D012518:Sarcomeres / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D020798:Two-Hybrid System Techniques
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D009124:Muscle Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; C578224:OBSCN protein, human; D017346:Protein Serine-Threonine Kinases