ISOLATION OF HUMAN AND MURINE HOMOLOGS OF THE DROSOPHILA MINIBRAIN GENE - HUMAN HOMOLOG MAPS TO 21Q22.2 IN THE DOWN-SYNDROME CRITICAL REGION

The presence of an extra copy of human chromosome 21 (trisomy 21), esp ecially region 21q22.2, causes many phenotypes in Down syndrome, inclu ding mental retardation. To study genes potentially responsible for so me of these phenotypes, we cloned a human candidate gene (DYRK) from 2 1q22.2 and its murine counterpart (Dyrk) that are homologous to the Dr osophila minibrain (mnb) gene required for neurogenesis and to the rat Dyrk gene (dual specificity tyrosine phosphorylation regulated kinase ). The three mammalian genes are highly conserved, >99% identical at t he protein level over their 763-amino-acid (aa) open reading frame; in addition, the mammalian genes are 83% identical over 414 aa to the sm aller 542-aa mnb protein. The predicted human DYRK and murine Dyrk pro teins both contain a nuclear targeting signal sequence, a protein kina se domain, a putative leucine zipper motif, and a highly conserved 13- consecutive-histidine repeat, Fluorescence in situ hybridization and r egional mapping data localize DYRK between markers D21S336 and D21S337 in the 21q22.2 region. Northern blot analysis indicated that both hum an and murine genes encode approximately 6-kb transcripts. PCR screeni ng of cDNA libraries derived from various human and murine tissues ind icated that DYRK and Dyrk are expressed both during development and in the adult. In situ hybridization of Dyrk to mouse embryos (13, 15, an d 17 days postcoitus) indicates a differential spatial and temporal pa ttern of expression, with the most abundant signal localized in brain gray matter, spinal cord, and retina. The observed expression pattern is coincident with many of the clinical findings in trisomy 21. Its ch romosomal locus (21q22.2), its homology to the mnb gene, and the in si tu hybridization expression patterns of the murine Dyrk combined with the fact that transgenic mice for a YAC to which DYRK maps are mentall y deficient suggest that DYRK may be involved in the abnormal neurogen esis found in Down syndrome. (C) 1996 Academic Press, Inc.