Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome "critical region".
The presence of an extra copy of human chromosome 21 (trisomy 21), especially region 21q22.2, causes many phenotypes in Down syndrome, including mental retardation. To study genes potentially responsible for some of these phenotypes, we cloned a human candidate gene (DYRK) from 21q22.2 and its murine counterpart (Dyrk) that are homologous to the Drosophila 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 the protein level over their 763-amino-acid (aa) open reading frame; in addition, the mammalian genes are 83% identical over 414 aa to the smaller 542-aa mnb protein. The predicted human DYRK and murine Dyrk proteins both contain a nuclear targeting signal sequence, a protein kinase domain, a putative leucine zipper motif, and a highly conserved 13-consecutive-histidine repeat. Fluorescence in situ hybridization and regional mapping data localize DYRK between markers D21S336 and D21S337 in the 21q22.2 region. Northern blot analysis indicated that both human and murine genes encode approximately 6-kb transcripts. PCR screening of cDNA libraries derived from various human and murine tissues indicated that DYRK and Dyrk are expressed both during development and in the adult. In situ hybridization of Dyrk to mouse embryos (13, 15, and 17 days postcoitus) indicates a differential spatial and temporal pattern 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 chromosomal locus (21q22. 2), its homology to the mnb gene, and the in situ hybridization expression patterns of the murine Dyrk combined with the fact that transgenic mice for a YAC to which DYRK maps are mentally deficient suggest that DYRK may be involved in the abnormal neurogenesis found in Down syndrome.
Song
W J
WJ
Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA. woojoo.song@umich.edu
Sternberg
L R
LR
Kasten-Sportès
C
C
Keuren
M L
ML
Chung
S H
SH
Slack
A C
AC
Miller
D E
DE
Glover
T W
TW
Chiang
P W
PW
Lou
L
L
Kurnit
D M
DM
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002874:Chromosome Mapping; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D004314:Down Syndrome / Q000235:genetics; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D005796:Genes; D005865:Gestational Age; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics; D051379:Mice / Q000235:genetics*; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011505:Protein-Tyrosine Kinases; D051381:Rats; D012160:Retina / Q000196:embryology / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013116:Spinal Cord / Q000196:embryology / Q000378:metabolism; D000097603:Dyrk Kinases
D005136:Eye Proteins; D009419:Nerve Tissue Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases