Truncations of Titin Causing Dilated Cardiomyopathy

被引：1022

作者：

Herman, Daniel S. ^{[1
]}

Lam, Lien ^{[1
,2
]}

Taylor, Matthew R. G. ^{[5
]}

Wang, Libin ^{[1
,2
]}

Teekakirikul, Polakit ^{[1
,3
]}

Christodoulou, Danos ^{[1
]}

Conner, Lauren ^{[1
]}

DePalma, Steven R. ^{[1
,2
]}

McDonough, Barbara ^{[1
,2
]}

Sparks, Elizabeth ^{[2
]}

Teodorescu, Debbie Lin ^{[3
]}

Cirino, Allison L. ^{[3
]}

Banner, Nicholas R. ^{[7
]}

Pennell, Dudley J. ^{[7
]}

Graw, Sharon ^{[6
]}

Merlo, Marco ^{[10
,11
]}

Di Lenarda, Andrea ^{[12
]}

Sinagra, Gianfranco ^{[10
,11
]}

Bos, J. Martijn ^{[13
,14
,15
]}

Ackerman, Michael J. ^{[13
,14
,15
]}

Mitchell, Richard N. ^{[4
]}

Murry, Charles E. ^{[16
,17
,18
]}

Lakdawala, Neal K. ^{[3
]}

Ho, Carolyn Y. ^{[3
]}

Barton, Paul J. R. ^{[7
,8
,9
]}

Cook, Stuart A. ^{[8
,9
]}

Mestroni, Luisa ^{[5
]}

Seidman, J. G. ^{[1
]}

Seidman, Christine E. ^{[1
,2
,3
]}

机构：

[1] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[2] Howard Hughes Med Inst, Boston, MA 02115 USA

[3] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA

[4] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[5] Univ Colorado, Cardiovasc Inst, Denver, CO 80202 USA

[6] Univ Colorado, Dept Psychiat, Denver, CO 80202 USA

[7] Univ London Imperial Coll Sci Technol & Med, Royal Brompton & Harefield Natl Hlth Serv Fdn Tru, London SW7 2AZ, England

[8] Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Clin Sci, London SW7 2AZ, England

[9] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW7 2AZ, England

[10] Osped Riuniti, Cardiovasc Dept, Trieste, Italy

[11] Univ Trieste, Trieste, Italy

[12] Azienda Serv Sanit 1, Ctr Cardiovasc, Trieste, Italy

[13] Mayo Clin, Dept Med, Rochester, MN USA

[14] Mayo Clin, Dept Pediat, Rochester, MN USA

[15] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN USA

[16] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

[17] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA

[18] Univ Washington, Dept Med Cardiol, Seattle, WA 98195 USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2012年 / 366卷 / 07期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

TIBIAL MUSCULAR-DYSTROPHY; MUSCLE FILAMENT TITIN; C-TERMINAL TITIN; CARDIAC-HYPERTROPHY; GENE; MUTATIONS; EXPRESSION; TENSION; DOMAIN; TTN;

D O I：

10.1056/NEJMoa1110186

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND Dilated cardiomyopathy and hypertrophic cardiomyopathy arise from mutations in many genes. TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size. METHODS We analyzed TTN in 312 subjects with dilated cardiomyopathy, 231 subjects with hypertrophic cardiomyopathy, and 249 controls by using next-generation or dideoxy sequencing. We evaluated deleterious variants for cosegregation in families and assessed clinical characteristics. RESULTS We identified 72 unique mutations (25 nonsense, 23 frameshift, 23 splicing, and 1 large tandem insertion) that altered full-length titin. Among subjects studied by means of next-generation sequencing, the frequency of TTN mutations was significantly higher among subjects with dilated cardiomyopathy (54 of 203 [27%]) than among subjects with hypertrophic cardiomyopathy (3 of 231 [1%], P = 3x10(-16)) or controls (7 of 249 [3%], P = 9x10(-14)). TTN mutations cosegregated with dilated cardiomyopathy in families (combined lod score, 11.1) with high (>95%) observed penetrance after the age of 40 years. Mutations associated with dilated cardiomyopathy were overrepresented in the titin A-band but were absent from the Z-disk and M-band regions of titin (P <= 0.01 for all comparisons). Overall, the rates of cardiac outcomes were similar in subjects with and those without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers (P = 4x10(-5)). CONCLUSIONS TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases. Incorporation of sequencing approaches that detect TTN truncations into genetic testing for dilated cardiomyopathy should substantially increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy. Defining the functional effects of TTN truncating mutations should improve our understanding of the pathophysiology of dilated cardiomyopathy. (Funded by the Howard Hughes Medical Institute and others.)

引用

页码：619 / 628

页数：10

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