Study suggests mechanism for heart defect that kills youn...( w.nature.com/ng/ ) and will appear in...)

w.nature.com/ng/ ) and will appear in the May issue of the journal. The online version includes video clips of silent heart embryos, which will be the first to be featured in Nature Genetics online publication history. (Video clips may also be viewed at http://www.ucsf.edu/dyrslab/sih_movies.html)

Our research demonstrates the key importance of TNNT2 in the sarcomere and shows, surprisingly, that its expression can affect the expression of two other proteins, said Amy Sehnert, MD, UCSF assistant professor of pediatric cardiology and lead author on the paper. This suggests new possibilities for the molecular pathways leading to the heart muscle problems seen in hypertrophic cardiomyopathy. Sehnert is a physician-scientist studying the molecular causes of heart diseases at the same time she treats them in the clinic.

She pursued zebrafish molecular genetics in collaboration with Stainier. Over the past seven years Stainier has identified the developmental role of more than ten vertebrate genes using the random mutagenesis technique in zebrafish. In this approach, adult male zebrafish are mutagenized, mated to female fish, and two generations later their tiny, transparent embryos are screened for abnormalities. Many pivotal early changes that take place in the human embryo can be witnessed in the zebrafish embryo which is also easy to manipulate genetically.

Once they had created a silent heart mutant, the scientists used two techniques to determine that embryos lacking this gene also fail to express two other contractile proteins in the heart. Using antibodies to search for the presence of contractile proteins, they found that one protein, troponin I was totally absent, and a second protein, tropomyosin, was dramatically reduced in the silent heart mutants. Gene level analysis showed a marked decrease in the expression of tropomyosin, suggesting for the first time that the expre
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Contact: Wallace Ravven
wravven@pubaff.ucsf.edu
415-476-2557
University of California - San Francisco
21-Apr-2002

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