Titin mutations as the molecular basis for dilated cardiomyopathy.

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.

[1]  廣井 知歳.  Polymorphisms in the SOD2 and HLA-DRB1 Genes Are Associated with nonfamilial Idiopathic Dilated Cardiomyopathy in Japanese , 2000 .

[2]  M. Gautel,et al.  A functional knock-out of titin results in defective myofibril assembly. , 2000, Journal of cell science.

[3]  H. Sorimachi,et al.  Muscle-specific Calpain, p94, Responsible for Limb Girdle Muscular Dystrophy Type 2A, Associates with Connectin through IS2, a p94-specific Sequence (*) , 1995, The Journal of Biological Chemistry.

[4]  J. Towbin,et al.  Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy. , 2000, The Journal of clinical investigation.

[5]  J. Seidman,et al.  The Genetic Basis for Cardiomyopathy from Mutation Identification to Mechanistic Paradigms , 2001, Cell.

[6]  S. Thibodeau,et al.  Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. , 1998, Science.

[7]  C. Macrae.  Genetics and dilated cardiomyopathy: limitations of candidate gene strategies. , 2000, European heart journal.

[8]  A. Matsumori,et al.  Characterization of the human nebulette gene: a polymorphism in an actin-binding motif is associated with nonfamilial idiopathic dilated cardiomyopathy , 2000, Human Genetics.

[9]  J. Towbin,et al.  The role of cytoskeletal proteins in cardiomyopathies. , 1998, Current opinion in cell biology.

[10]  J. Ross,et al.  Adult mice deficient in actinin–associated LIM-domain protein reveal a developmental pathway for right ventricular cardiomyopathy , 2001, Nature Medicine.

[11]  B Maisch,et al.  Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. , 1996, Circulation.

[12]  M. Kamisago.  Mutations in Sarcomere Protein Genes as a Cause of Dilated Cardiomyopathy , 2000 .

[13]  T. Sasazuki,et al.  Novel missense mutation in cardiac ? myosin heavy chain gene found in a japanese patient with hypertrophic cardiomyopathy , 1992 .

[14]  A. Beggs.  Dystrophinopathy, the expanding phenotype. Dystrophin abnormalities in X-linked dilated cardiomyopathy. , 1997, Circulation.

[15]  G. Lanfranchi,et al.  Telethonin, a novel sarcomeric protein of heart and skeletal muscle , 1997, FEBS letters.

[16]  永野 敦.  Emerin deficiency at the nuclear membrane in patients with Emery-Dreifuss muscular dystrophy , 1996 .

[17]  M Hiroe,et al.  Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. , 1999, Biochemical and biophysical research communications.

[18]  Siegfried Labeit,et al.  The NH2 Terminus of Titin Spans the Z-Disc: Its Interaction with a Novel 19-kD Ligand (T-cap) Is Required for Sarcomeric Integrity , 1998, The Journal of cell biology.

[19]  K. Suzuki,et al.  Tissue-specific expression and alpha-actinin binding properties of the Z-disc titin: implications for the nature of vertebrate Z-discs. , 1997, Journal of molecular biology.

[20]  Paul Young,et al.  Structural basis for activation of the titin kinase domain during myofibrillogenesis , 1998, Nature.

[21]  Minoru Hongo,et al.  MLP-Deficient Mice Exhibit a Disruption of Cardiac Cytoarchitectural Organization, Dilated Cardiomyopathy, and Heart Failure , 1997, Cell.

[22]  B. Lowes,et al.  Dilated cardiomyopathy associated with deficiency of the cytoskeletal protein metavinculin. , 1996, Circulation.

[23]  T. Irving,et al.  Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments. , 1995, Biophysical journal.

[24]  D. Kelsell,et al.  Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. , 2000, Human molecular genetics.

[25]  J A Osborne,et al.  Familial dilated cardiomyopathy locus maps to chromosome 2q31. , 1999, Circulation.

[26]  A. Crosby,et al.  Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease) , 2000, The Lancet.

[27]  T. Sasazuki,et al.  DNA typing of HLA class II genes in Japanese patients with dilated cardiomyopathy. , 1995, Journal of molecular and cellular cardiology.

[28]  Y. Murakami,et al.  Both hypertrophic and dilated cardiomyopathies are caused by mutation of the same gene, delta-sarcoglycan, in hamster: an animal model of disrupted dystrophin-associated glycoprotein complex. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Ernest S. Kawasaki,et al.  Detection of Gene Expression , 1989 .

[30]  C. Seidman,et al.  Many roads lead to a broken heart: the genetics of dilated cardiomyopathy. , 2001, American journal of human genetics.

[31]  J. Seidman,et al.  Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. , 1999, The New England journal of medicine.

[32]  Pei-shan Wu,et al.  Biochemical and Biophysical Research Communications , 1960, Nature.

[33]  H. Yajima,et al.  The N-Terminal Z Repeat 5 of Connectin/Titin Binds to the C-Terminal Region of α-Actinin , 1997 .

[34]  P. Burch,et al.  Desmin mutation responsible for idiopathic dilated cardiomyopathy. , 1999, Circulation.

[35]  E. Maestrini,et al.  A novel X-linked gene, G4.5. is responsible for Barth syndrome , 1996, Nature Genetics.

[36]  M. Gautel,et al.  Molecular structure of the sarcomeric Z‐disk: two types of titin interactions lead to an asymmetrical sorting of α‐actinin , 1998, The EMBO journal.

[37]  A. Tajik,et al.  The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. , 1992, The New England journal of medicine.

[38]  H. Granzier,et al.  Cardiac titin isoforms are coexpressed in the half-sarcomere and extend independently. , 2001, American journal of physiology. Heart and circulatory physiology.

[39]  S. Solomon,et al.  Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. , 2001, The New England journal of medicine.

[40]  Siegfried Labeit,et al.  Titins: Giant Proteins in Charge of Muscle Ultrastructure and Elasticity , 1995, Science.

[41]  M. Gautel,et al.  The central Z-disk region of titin is assembled from a novel repeat in variable copy numbers. , 1996, Journal of cell science.

[42]  K Suzuki,et al.  Functional Defects of a Muscle-specific Calpain, p94, Caused by Mutations Associated with Limb-Girdle Muscular Dystrophy Type 2A* , 1998, The Journal of Biological Chemistry.

[43]  Mutations in the human δ-sarcoglycan gene in familial and sporadic dilated cardiomyopathy , 2000 .

[44]  F. Muntoni,et al.  Brief report: deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. , 1993, The New England journal of medicine.

[45]  R. Higuchi.  Using PCR to Engineer DNA , 1989 .

[46]  Dietmar Labeit,et al.  The Complete Gene Sequence of Titin, Expression of an Unusual ≈700-kDa Titin Isoform, and Its Interaction With Obscurin Identify a Novel Z-Line to I-Band Linking System , 2001 .