DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways

Down syndrome is one of the major causes of mental retardation and congenit al heart malformations. Other common clinical features of Down syndrome inc lude gastrointestinal anomalies, immune system defects and Alzheimer's dise ase pathological and neurochemical changes. The most likely consequence of the presence of three copies of chromosome 21 is the overexpression of its resident genes, a fact which must underlie the pathogenesis of the abnormal ities that occur in Down syndrome. Here we shaw that DSCR1, the product of a chromosome 21 gene highly expressed in brain, heart and skeletal muscle, is overexpressed in the brain of Down syndrome fetuses, and interacts physi cally and functionally with calcineurin A, the catalytic subunit of the Ca2 +/calmodulin-dependent protein phosphatase PP2B, The DSCR1 binding region i n calcineurin A is located in the linker region between the calcineurin A c atalytic domain and the calcineurin B binding domain, outside of other func tional domains previously defined in calcineurin A. DSCR1 belongs to a fami ly of evolutionarily conserved proteins with three members in humans: DSCR1 , ZAKI-4 and DSCR1L2, We further demonstrate that overexpression of DSCR1 a nd ZAKI-4 inhibits calcineurin-dependent gene transcription through the inh ibition of NF-AT translocation to the nucleus. Together, these results sugg est that members of this newly described family of human proteins are endog enous regulators of calcineurin-mediated signaling pathways and as such, th ey may be involved in many physiological processes.