STRUCTURAL MUTATIONS IN TITIN CAUSE DILATED CARDIOMYOPATHY
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IPC분류정보
국가/구분
United States(US) Patent
공개
국제특허분류(IPC7판)
C12Q-001/68
C12N-009/12
출원번호
US-0111308
(2012-04-11)
공개번호
US-0199284
(2014-07-17)
국제출원번호
PCT/US12/33122
(2012-04-11)
§371/§102 date
20140224
(20140224)
발명자
/ 주소
Seidman, Jonathan G.
Seidman, Christine E.
Herman, Daniel E.
출원인 / 주소
PRESIDENT AND FELLOWS OF HARVARD COLLEGE
인용정보
피인용 횟수 :
0인용 특허 :
0
초록▼
Provided herein are diagnostic markers and methods for identifying a subject having an increased susceptibility for developing or having dilated cardiomyopathy. The method comprises determining if the subject has a mutation in the TTN nucleic as acid or titin polypeptide. Further provided herein are
Provided herein are diagnostic markers and methods for identifying a subject having an increased susceptibility for developing or having dilated cardiomyopathy. The method comprises determining if the subject has a mutation in the TTN nucleic as acid or titin polypeptide. Further provided herein are methods of treating subjects having or at risk of having dilated cardiomyopathy.
대표청구항▼
1.-44. (canceled) 45. An assay comprising: (i) contacting a nucleic acid sample obtained from a subject with a probe, wherein the probe is capable of detecting a mutation resulting in a truncated TITIN polypeptide;(ii) detecting the presence of the mutation in the nucleic acid sample, and(iii) deter
1.-44. (canceled) 45. An assay comprising: (i) contacting a nucleic acid sample obtained from a subject with a probe, wherein the probe is capable of detecting a mutation resulting in a truncated TITIN polypeptide;(ii) detecting the presence of the mutation in the nucleic acid sample, and(iii) determining the subject has an increased risk for developing dilated cardiomyopathy (DCM) or in need of treatment for DCM if at least one mutation is detected in (ii). 46. The assay of claim 45, wherein the probe is a sequencing primer. 47. The assay of claim 11, wherein detecting the presence of the mutation comprises: (i) sequencing at least a portion of TTN gene in a sample from a human subject;(ii) comparing the sequence obtained in step (i) with wild type TTN gene sequence having a nucleic acid sequence set forth in SEQ ID NO: 1. 48. The assay of claim 45, wherein the truncated TITIN polypeptide lacks part of A-band having a wild-type sequence set forth in SEQ ID NO: 725. 49. The assay of claim 45, wherein the mutation is selected from the group consisting of 6247—6247delG, 12745C>T, 14470—14471insCACACTCCATA (SEQ ID NO: 722), 19183—19183delG, 23798—23810de1GTCAAGATATCTG (SEQ ID NO: 723), 38621—38622insA, 44336—44336delA, 45322—45322delT, 49077G>A, 51883C>T, 52408C>T, 53145—53146insG, 53347G>T, 53935—53935delC, 56367T>A, 56572C>T, 56953C>T, 58678C>T, 59530C>T, 61046—61046delC, 65867—65867delA, 67057—67063de1GCATATGinsTA, 67745—67745delT, 72178—72179insT, 72723—72739delinsAGA, 77065C>T, 79896G>A, 80845C>T, 81046A>T, 81440G>A, 81536—81537delCT, 82701C>A, 84977—84980delATTA, 87953G>A, 88242C>T, 88528G>T, 89177—89181delAAATT, 90241C>T, 91042—91042delA, 91537—91538insA, 94111A>T, 95522C>A, 30476-1G>A, 34186+1G>T, 35635G>C, 35635+1G>A, 44725+2delT, 48364+1G>T, 50346—+3A>G, 54422-5T>A, 54704-1G>A, 55003+1G>A, 62425+5G>A, 63405A>G, 64489+1G>A, 81898+2T>A, 92569+1G>C, and any combination thereof, wherein the mutation location is determined based upon the wildtype TTN sequence having a nucleic acid sequence set forth in SEQ ID NO: 1. 50. The assay of claim 45, wherein dilated cardiomyopathy is idiopathic dilated cardiomyopathy or heart failure or any other related cardiomyopathy. 51. A method of treating a subject for dilated cardiomyopathy (DCM), comprising: a. Selected a subject in need of treatment for DCM using an assay comprising: i. contacting a nucleic acid sample obtained from a subject with a probe, wherein the probe is capable of detecting a mutation resulting in a truncated TITIN polypeptide;ii. detecting the presence of the mutation in the nucleic acid sample, andb. administering a treatment for DCM if at least one mutation is detected in (ii). 52. The method of claim 51, wherein the treatment is selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, beta blockers, diuretics, aldosterone antagonists, digoxin (Lanoxin), blood thinning medications, biventricular pacemakers, implantable cardioverter-defibrillators (ICDs), heart pumps (left ventricular assist devices, or LVADs), heart transplant, gene therapy, calcium channel blockers, tissue growth factor inhibitors, and any combinations thereof. 53. The method of claim 51, wherein the treatment comprises administering to said subject a polypeptide comprising amino acid SEQ ID NO: 2 or a nucleic acid encoding a polypeptide comprising amino acid SEQ ID NO: 2. 54. The method of claim 53, wherein the nucleic acid encoding the polypeptide of amino acid SEQ ID NO: 2 is operably linked to a vector. 55. The method of claim 51, wherein the truncated TITIN polypeptide lacks part of the A-band, having a wild-type sequence set forth in SEQ ID NO: 725. 56. The method of claim 51, wherein the mutation is selected from the group consisting of 6247—6247delG, 12745C>T, 14470—14471insCACACTCCATA (SEQ ID NO: 722), 19183—19183delG, 23798—23810de1GTCAAGATATCTG (SEQ ID NO: 723), 38621—38622insA, 44336—44336delA, 45322—45322delT, 49077G>A, 51883C>T, 52408C>T, 53145—53146insG, 53347G>T, 53935—53935delC, 56367T>A, 56572C>T, 56953C>T, 58678C>T, 59530C>T, 61046—61046delC, 65867—65867delA, 67057—67063de1GCATATGinsTA, 67745—67745delT, 72178—72179insT, 72723—72739delinsAGA, 77065C>T, 79896G>A, 80845C>T, 81046A>T, 81440G>A, 81536—81537delCT, 82701C>A, 84977—84980delATTA, 87953G>A, 88242C>T, 88528G>T, 89177—89181delAAATT, 90241C>T, 91042—91042delA, 91537—91538insA, 94111A>T, 95522C>A, 30476-1G>A, 34186+1G>T, 35635G>C, 35635+1G>A, 44725+2delT, 48364+1G>T, 50346—+3A>G, 54422-5T>A, 54704-1G>A, 55003+1G>A, 62425+5G>A, 63405A>G, 64489+1G>A, 81898+2T>A, 92569+1G>C, and any combination thereof, wherein the mutation location is determined based upon the wildtype TTN sequence having a nucleic acid sequence set forth in SEQ ID NO: 1. 57. The method of claim 51, wherein detection of the mutation is by nucleic acid sequencing. 58. The method of claim 51, wherein dilated cardiomyopathy is idiopathic dilated cardiomyopathy. 59. A method of treating a subject for dilated cardiomyopathy (DCM), comprising administering a treatment for DCM to a subject determined to have a mutation resulting in a truncated TITIN polypeptide and not administering a treatment for DCM to a subject determined not to have a mutation resulting in a truncated TITIN polypeptide.
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