Dyrk kinase and Congenital Heart Disease in Downs Syndrome

Doctor's Name: 
Ching-Pin Chang, M.D.
Stanford University

Dr. Chang and colleagues propose to study the normal function of the Dyrk1a gene during fetal development. The questions to be addressed include: Is this gene essential for normal heart development ? Would NFAT genes gain function in the absence of Dyrk1a ? Finally, Dr. Chang and colleagues will reduce one copy of Dyrk1a in mouse models of Downs Syndrome ( DS ) and investigate whether normalization of Dyrk1a gene dosage can rescue heart defects in those mice. This will establish the roles of Dyrk1a overdosage in the pathogenesis of DS. The search for genes implicated in the pathogenesis of DS has led to the concept of a Downs Syndrome Critical Region ( DSCR ). The DSCR is the smallest region triplicated in all established cases of DS. Recently two genes, DSCR1 and Dyrk1a, within this critical region of chromosome 21 were shown to synergize to disrupt NFAT gene function. The NFAT genes are important to coordinate cell-cell interactions during fetal development. Mice with mutations in the NFAT genes produce many features of DS. These observations suggest that extra copies of DSCR1 and Dyrk1a present on human chromosome 21 results in the pathological features of DS. It is therefore important to study how extra copies of these two genes disrupt NFAT function and how that leads to DS. These studies will lead to the identification of new therapeutic targets and the design of new diagnostic and prognostic methods. DS is the leading cause of congenital heart disease in children. DS patients have extra copies of many genes on chromosome 21. This is called Trisomy 21. Trisomy 21 occurs at a frequency of 1 in 43 spontaneous abortions and 1 in 750 live births. The characteristics of the disease include mental retardation, specific craniofacial features and congenital heart disease. Congenital heart malformations occur in approximately 60% of DS. Due to it’s high prevalence, DS is a major cause of congenital heart disease affecting millions of children worldwide.

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