Harvard College

The Brigham and Women's Hospital, Inc.

Dana-farber-cancer Institute Inc.

T Cell Sciences, Inc.

Cell Genesys, Inc.

T Cell Diagnostics, Inc.

Jonathan G Seidman

Jack L Strominger

Michael B Brenner

Stephen H Ip

Michael S Krangel

Christine E Seidman

Hugh Watkins

Calum McRae

Ludwig Thierfelder

Aya Jakobovits

Huntington Potter

Wei Zhang

Daniel E Herman

Hamid Band

Usamah S Kagyali

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.

Structural mutations in titin cause dilated cardiomyopathy

The present invention relates to a method of identifying drugs or agents which have immuno-suppressive effects through or as a result of their effect on calcineurin, including drugs which affect the calcineurin A&agr; (CNA&agr;) subunit or the calcineurin A&bgr; (CNA&bgr;) subunit. In addition, the present invention relates to a method of identifying drugs which reduce (partially or totally) phosphorylation of the microtubule-associated protein tau, in the nervous system of a mammal; a method of identifying drugs which reduce (partially or totally) paired helical filament formation in the nervous system of a mammal; and a method of identifying drugs which reduce (partially or totally) formation of paired helical filaments, amyloid deposits or both. The present invention also relates to transgenic non-human mammals, such as rodents and particularly mice, which lack a functional calcineurin gene and, thus, have disyrupted calcineurin expression.

Methods for assessing the role of calcineurin immunosuppression and neurotoxicity

The invention pertains to methods for detecting the presence or absence of a mutation associated with hypertrophic cardiomyopathy (HC). The methods include providing DNA which encodes a sarcomeric thin filament protein (e.g., .alpha.-tropomyosin or cardiac troponin T) and detecting the presence or absence of a mutation in the amplified product which is associated with HC. DNA encoding an actin-associated protein, a myosin-associated protein, or a sarcomeric protein other than .beta. cardiac heavy chain can also be used in the methods of the present invention. The invention further pertains to methods for diagnosing familial HC (FHC) in a subject. These methods typically include obtaining a sample of DNA which encodes a sarcomeric thin filament protein from a subject being tested for FHC and diagnosing the subject for FHC by detecting the presence or absence of a mutation in the sarcomeric thin filament protein which causes FHC as an indication of the disease. An alternative method for diagnosing HC includes obtaining a sample of at least two sarcomeric proteins from a subject being tested for HC and diagnosing the subject for HC by detecting an abnormality in the sarcomeric proteins as an indication of the disease. Other aspects of the invention include kits useful for diagnosing HC and methods for treating HC.

Methods for detecting mutations associated with hypertrophic

Homozygotic cells are obtained by employing homologous recombination with a construct comprising a marker gene. The marker gene allows for selection without amplification and by employing elevated levels of the antibiotic to which the marker gene imparts resistance, gene conversion can occur, where in a diploid host, both copies of the target locus will be the same. In this manner, knock-outs of genes can be readily achieved without requiring two steps of homologous recombination.

Cells homozygous for disrupted target loci

The present invention provides purified polypeptides which comprise at least a portion of a .delta.T cell receptor polypeptide, a .gamma.T cell receptor polypeptide or a .gamma.,.delta. T cell receptor complex. Substances capable of forming complexes with these polypeptides are also provided. Additionally, methods for detecting T cells which have within them or on their surfaces a polypeptide of the present invention are provided. Moreover, methods for diagnosing immune system abnormalities are provided which comprise measuring in a sample from a subject the number of T cells which have within them or on their surfaces a polypeptide of the present invention.

Method for detecting the .gamma.,.delta. T cell receptor

The present invention is directed to purified polypeptides comprising the .gamma. T cell antigen receptor (TCR) polypeptide, the .delta. TCR polypeptide, a .gamma., .delta. TCR complex, or a fragment thereof containing an epitope. The invention also relates to nucleic acid sequences encoding such polypeptides, and subsequences thereof. In specific embodiments, the invention relates to nucleic acid sequences comprising variable, diversity, joining, or constant regions of the .delta. TCR gene sequence. The invention also relates to monoclonal antibodies specifically reactive with an epitope of the gamma or delta TCR polypeptides. In specific embodiments, these antibodies are reactive with the delta constant region, the delta variable region, or gamma constant region. Such antibodies can be identified by detecting co-modulation of the CD3 antigen. In another embodiment, the invention relates to compositions comprising substantially purified cells which express both a .gamma., .delta. TCR and the CD4 antigen. The invention also relates to a composition comprising cells which express a .gamma., .delta. TCR that is not associated with a CD3 complex.

Human .gamma., .delta.T cell antigen receptor polypeptides and nucleic

The present invention provides purified polypeptides which comprises at least a portion of a a .delta.T cell receptor polypeptide, a .gamma.T cell receptor polypeptide, a .gamma..delta.T cell receptor complex or a .gamma..delta.T cell receptor complex. Substances capable of forming complexes with these polypeptides are also provided. Additonally, methods for detecting T cells which have within them or on their surfaces a polypeptide of the present invention are provided. Moreover, methods for diagnosing immune system abnormalities are provided which comprise measuring in a sample from a subject the number of T cells which have within them or on their surfaces a polypeptide of the present invention.

Nucleic acids encoding the delta chain of the T cell antigen receptor

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Milton, MA, United States of America

Jonathan G Seidman