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Many unrelated patients with the disorder for mutation in human desmosomal cadherin desmocollin-2 (DSC2) are investigated. The results have identified DSC2 mutations as a cause of arrhythmogenic right ventricular cardiomyopathy (ARVC) in humans and have shown that physiologic levels of DSC2 are crucial for normal cardiac desmosome formation, early cardiac morphogenesis and cardiac function.

We report that Id knockout mouse embryos display multiple cardiac defects, but mid-gestation lethality is rescued by the injection of 15 wild-type embryonic stem (ES) cells into mutant blastocysts. Myocardial markers altered in Id mutant cells are restored to normal throughout the chimeric myocardium. Intraperitoneal injection of ES cells into female mice before conception also partially rescues the cardiac phenotype with no incorporation of ES cells. Insulin-like growth factor 1, a long-range secreted factor, in combination with WNT5a, a locally secreted factor, likely account for complete reversion of the cardiac phenotype. Thus, ES cells have the potential to reverse congenital defects through Id-dependent local and long-range effects in a mammalian embryo., The Id proteins are dominant negative antagonists of basic helix-loop-helix (bHLH) transcription factors and regulate differentiation in multiple lineages (1). Previous studies have shown that Id1 to Id4 are expressed [...]

Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by cardiac and extracardiac myxomas in the setting of spotty skin pigmentation and endocrinopathy. We previously identified PRKAR1A (regulatory subunit 1[alpha] of protein kinase A) mutations in CNC. Mutational analyses of the PRKAR1A gene in 51 unrelated CNC probands now detect mutations in 65%. All mutations, except for one unique missense mutation, lead to PRKAR1A haploinsufficiency. Therefore, we studied the consequences of prkar1a haploinsufficiency in mice, Although we did not observe cardiac myxomas or altered pigmentation in [prkar1a.sup.+/-] mice, we did observe some phenotypes similar to CNC, including altered heart rate variability. Moreover, [prkar1a.sup.+/-] mice exhibited a marked propensity for extracardiac tumorigenesis. They developed sarcomas and hepatocellular carcinomas. Sarcomas were frequently associated with myxomatous differentiation. Tumors from [prkar1a.sup.+/-] mice did not exhibit prkar1a loss of heterozygosity. Thus, we conclude that although PRKAR1A haploinsufficiency does predispose to tumorigenesis, distinct secondary genetic events are required for tumor formation.

The R6740 mutation of the MYH8 gene encoding perinatal myosin heavy chain causes a variant form of the carney complex associated with distal arthrogryposis, which includes typical spotty pigmentation of the skin, familial cardiac and cutaneous myxoma, and endocrinopathy. Novel roles for perinatal myosin in both the development of skeletal muscle and cardiac tumorigenesis are demonstrated.

A 27-year-old woman who began having episodes of fainting was found to have a heart tumor called a cardiac myxoma. She also had a history of Cushing's disease and freckles. She was diagnosed with a medical syndrome called Carney complex.

A mutation in the gene for the gamma2 regulatory subunit of AMP-activated protein kinase has been linked to a heart arrhythmia called Wolff-Parkinson-White syndrome. The arrhythmia is caused by an abnormal electrical pathway between the upper and lower parts of the heart.

To better understand the role of TBX5, a T-box containing transcription factor in forelimb and heart development, we have studied the clinical features of Holt-Oram syndrome caused by 10 different TBX5 mutations. Defects predicted to create null alleles caused substantial abnormalities both in limb and heart. In contrast, missense mutations produced distinct phenotypes: Gly80Arg caused significant cardiac malformations but only minor skeletal abnormalities; and Arg237Gln and Arg237Trp caused extensive upper limb malformations but less significant cardiac abnormalities. Amino acids altered by missense mutations were located on the three-dimensional structure of a related T-box transcription factor, Xbra, bound to DNA. Residue 80 is highly conserved within T-box sequences that interact with the major groove of target DNA; residue 237 is located in the T-box domain that selectively binds to the minor groove of DNA. These structural data, taken together with the predominant cardiac or skeletal phenotype produced by each missense mutation, suggest that organ-specific gene activation by TBX5 is predicated on biophysical interactions with different target DNA sequences.

Holt-Oram syndrome may be caused by mutations in a gene on chromosome 12q2. Holt-Oram syndrome is an inherited disorder characterized by skeletal deformities and heart defects. Researchers performed clinical and genetic-linkage studies on two large, unrelated families with the syndrome. In Family A, 26 of 49 members were affected and 18 surviving members were evaluated. All affected members of Family A had skeletal abnormalities and cardiovascular disease. Eleven had heart conduction diseases. In Family B, 18 of 31 affected members were still alive for examination. All affected family members had skeletal abnormalities and had severe skeletal deformities more frequently than affected members of Family A. In contrast, Family B had less severe and less frequent cardiovascular disease than Family A and only one member had a heart conduction disease. Genetic analysis revealed a linkage of the syndrome to mutations on chromosome 12.

More than half the number of patients suffering from congestive heart failure (CHF) die by ventricular tachycardia. Most patients do not survive beyond a year after receiving the diagnosis.

Radiofrequency catheter ablation treatment may be effective for treating Wolff-Parkinson-White syndrome even if the patient has no symptoms, according to a study published in 2003. Other studies have shown that these patients have a low risk of sudden death from a severe arrhythmia. So many doctors decided not to treat them. This study shows that this decision may need to be reconsidered.

Mutations in human TBXS, a member of the T-box transcription factor gene family, cause congenital cardiac septation defects and isomerism in autosomal dominant Holt-Oram syndrome. To determine the cellular function of TBX5 in cardiogenesis, we overexpressed wild-type and mutant human TBX5 isoforms in vitro and in vivo. TBX5 inhibited cell proliferation of D17 canine osteosarcoma cells and MEQC quail cardiomyocyte-like cells in vitro. Mutagenesis of the 5' end of the T-box but not the 3' end of the T-box abolished this effect. Overexpression of TBX5 in embryonic chick hearts showed that TBX5 inhibits myocardial growth and trabeculation. TBX5 effects in vivo were abolished by Gly80Arg missense mutation of the 5' end of the T-box. PCNA analysis in transgenic chick hearts revealed that TBX5 overexpression does suppress embryonic cardiomyocyte proliferation in vivo. Inhibitory effects of TBX5 on cardiomyocyte proliferation include a noncell autonomous process in vitro and in vivo. TBX5 inhibited proliferation of both nontransgenic cells cocultured with transgenic cells in vitro and nontransgenic cardiomyocytes in transgenic chick hearts with mosaic expression of TBX5 in vivo. Immunohistochemical studies of human embryonic tissues, including hearts, also demonstrated that TBX5 expression is inversely related to cellular proliferation. We propose that TBX5 can act as a cellular arrest signal during vertebrate cardiogenesis and thereby participate in modulation of cardiac growth and development.

Author(s): Cathy J. Hatcher [1]; Craig T. Basson [1] T-box transcription factors comprise an ancient gene family [1] that contributes to the embryonic development of many organ systems. Heritable abnormalities [...]

Author(s): Craig T. Basson [1] The Shape of the Heart by Pierre J. Vinken Elsevier Science, 206 pp, $20.00 The scalloped-shaped "Valentine's" heart is a ubiquitous icon in Western culture. [...]