A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart

Abstract

Down syndrome is a major cause of mental retardation and congenital heart defects. While most of the affected individuals have three copies of chromosome 21, patients with partial trisomy 21 have also been described. These rare cases define a minimal region for the Down syndrome phenotype encompassing about 3 Mb around D21S55. By using a new method for the identification of coding sequences (Alu-splice PCR) we have identified a new gene, DSCR1, from region 21q22.1-q22.2. DSCR1 encodes a novel protein which has an acidic domain, a serine-proline motif, a putative DNA binding domain and a proline-rich region with the characteristics of a SH3 domain ligand. These features suggest that DSCR1 could be involved in transcriptional regulation and/or signal transduction. DSCR1 is highly expressed in human brain and heart, and increased expression in the brains of young rats compared with adults suggests a role for DSCR1 during central nervous system development. Structural characteristics, together with its particular expression in brain and heart, encourage us to suggest that the overexpression of DSCR1 may be involved in the pathogenesis of Down syndrome, in particular mental retardation and/or cardiac defects.

Upregulation of threeDrosophilahomologs of human chromosome 21 genes alters synaptic function: Implications for Down syndrome

“…Using Drosophila as a model system, we have previously shown that nebula (nla), the Drosophila ortholog of DS critical region 1 (DSCR1), also called regulator of calcineurin 1 (RCAN1) (11,12), binds to and inhibits the phosphatase activity of calcineurin, a protease involved in various biological pathways including learning and memory, and that altering the level of nebula leads to defective learning through calcineurin-mediated signaling (13). Among the many targets of calcineurin is synaptojanin (synj), a phosphatidylinositol phosphatase implicated in endocytosis (14).…”

Dual roles of modulatory calcineurin-interacting protein 1 in cardiac hypertrophy

“…Modulatory calcineurin-interacting protein (MCIP)1, first cloned as the product of the Down syndrome critical region 1 (DSCR1) gene on chromosome 21 (11), interacts with the catalytic A subunit of calcineurin and inhibits its phosphatase activity (12). Although we initially termed the protein myocyte-enriched calcineurin-interacting protein 1, its expression is not limited to muscle and its biological function is unlikely limited to muscle tissues.…”

Spatial and Intracellular Distribution of the Endogenous Calcineurin-Inhibitory Proteins, ZAKI-4, in Mouse Brain

“…The abundant expression of ZAKI-4 isoforms in brain is distinct among endogenous calcineurin inhibitors that contain an ISPPxSPP motif. Though Fuentes et al [7] demonstrated that DSCR1 mRNA was also expressed in brain, the expression level was much lower than in the heart and skeletal muscles [8]. Similarly, the expression of DSCR1L2 mRNA was also low in the brain [27].…”

“…In mammalian tissues, DSCR1 Down Syndrome Candidate Region 1 [7] (also designated as MCIP1 [24] or Adapt 78 [6]) and DSCRlL2 [27] are included in this family. Calcineurin is a calcium/calmodulin-dependent serine/threonine phosphatase, consisting of a 60-kDa catalytic subunit A and 19-kDa calcium-binding regulatory subunit B [reviewed in 25].…”