Critical role of the D21S55 region on chromosome 21 in the pathogenesis of Down syndrome.

Rahmani, Zohra; Blouin, Jean‐Louis; Créau-Goldberg, N.; Watkins, Paul C.; Mattéi, Jean-François; Poissonnier, M; Prieur, M; Chettouh, Zoubida; Nicole, Annie; Aurias, Alain

doi:10.1073/pnas.86.15.5958

Cited by 228 publications

(119 citation statements)

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“…In situ hybridization studies show that DYRK1A is highly expressed in brain gray matter, spinal cord, and retina in developing murine embryos (Song et al, 1996;Rahmani et al, 1998;Hämmerle et al, 2003a;Mao et al, 2003;Marti et al, 2003) and in the cerebral cortex, cerebellum, and pyramidal cell layer in the hippocampus in adult mice (Guimera et al, 1996). DYRK1A has been considered a good candidate gene for the Down syndrome phenotypic abnormalities (reviewed in Epstein, 2000;Vicari et al, 2000;Nadel, 2003) due to its localization in the Down syndrome critical region of chromosome 21 (Rahmani et al, 1989(Rahmani et al, , 1990Delabar et al, 1993;Shindoh et al, 1996;Song et al, 1996), its overexpression in the brain of Down syndrome patients (Guimera et al, 1999), and the neurobehavioral alterations shown by transgenic mice overexpressing the gene (Smith and Rubin, 1997;Altafaj et al, 2001). The recent observation that the size of dendrites in some brain areas is reduced in DYRK1A haploinsufficient mice indicates that DYRK1A dose reduction could affect the length and the complexity of the dendrites (Fotaki et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…The human Dyrk1A gene maps to the 21q22.2 region of chromosome 21, in the Down syndrome critical region (Rahmani et al, 1989(Rahmani et al, , 1990Delabar et al, 1993;Shindoh et al, 1996;Song et al, 1996), and transgenic mice harboring an extra copy of this gene exhibit cognitive deficits and motor abnormalities characteristic of Down syndrome (Smith and Rubin, 1997;Altafaj et al, 2001). The human and rodent Dyrk1A gene are ubiquitously expressed in adult and fetal tissues with high expression in the brain and the heart during development (Guimera et al, 1996(Guimera et al, , 1999Song et al, 1996;Rahmani et al, 1998;Hämmerle et al, 2003a;Mao et al, 2003;Marti et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1

Kelly

Rahmani

2005

MBoC

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Dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) is the human homologue of the Drosophila mnb (minibrain) gene. In Drosophila, mnb is involved in postembryonic neurogenesis. In human, DYRK1A maps within the Down syndrome critical region of chromosome 21 and is overexpressed in Down syndrome embryonic brain. Despite its potential involvement in the neurobiological alterations observed in Down syndrome patients, the biological functions of the serine/threonine kinase DYRK1A have not been identified yet. Here, we report that DYRK1A overexpression potentiates nerve growth factor (NGF)-mediated PC12 neuronal differentiation by up-regulating the Ras/MAP kinase signaling pathway independently of its kinase activity. Furthermore, we show that DYRK1A prolongs the kinetics of ERK activation by interacting with Ras, B-Raf, and MEK1 to facilitate the formation of a Ras/B-Raf/MEK1 multiprotein complex. These data indicate that DYRK1A may play a critical role in Ras-dependent transducing signals that are required for promoting or maintaining neuronal differentiation and suggest that overexpression of DYRK1A may contribute to the neurological abnormalities observed in Down syndrome patients. INTRODUCTIONMinibrain (mnb)/dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) gene is a member of a growing family of protein kinases called DYRK. In Drosophila, mnb seems to play an essential role during postembryonic neurogenesis. Mutant flies are characterized by a marked reduction in size of the adult optic lobes and the central brain hemispheres. This is caused by the abnormal spacing of neuroblasts and a reduction in the production of neuronal progeny (Tejedor et al., 1995). At least seven closely related homologous mammalian kinases in the DYRK family have since been isolated (Guimera et al., 1996(Guimera et al., , 1999Shindoh et al., 1996;Song et al., 1996Song et al., , 1997Raich et al., 2003). The DYRK family possesses serine and threonine phosphorylation activity as well as autophosphorylation activity on tyrosine residues (Kentrup et al., 1996;Becker et al., 1998;Becker and Joost, 1999;Himpel et al., 2000). Their kinase activity is dependent on the YXY motif in the activation loop of the catalytic domain, which is located at the same position as the characteristic TXY motif of the mitogen-activated protein kinases (MAPKs), suggesting an activation mechanism similar to that of the MAPK (Himpel et al., 2000). Closely related enzymes in lower eukaryotes also have been isolated, including Yak1p in Saccharomyces cerevisiae (Garrett and Broach, 1989), Pom1p in Schizosaccharomyces pombe (Bahler and Pringle, 1998), and YakA in Dictyostelium discoideum (Van Es et al., 2001). Although not much is known about their cellular functions, they all seem to be involved in the regulation of the cell growth and/or development.In the DYRK family, DYRK1A has been the best characterized to date. The human Dyrk1A gene maps to the 21q22.2 region of chromosome 21, in the Down syndrome critical region (Rah...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1

Kelly

Rahmani

2005

MBoC

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“…The earliest studies hypothesized that a relatively small region of HSA21 may play a major role in DS phenotypes, and proposed the concept of a DS critical region (DSCR). 4,7,18,19 The DSCR was defined with a proximal boundary between markers D21S17 (35 892 kb) and D21S55 (38 012 kb), and a distal boundary at MX1 (41 720 kb). 5,8 This is a region spanning 3.8 -6.5 Mb and containing B25 -50 genes.…”

Section: Introductionmentioning

confidence: 99%

Genotype–phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21

et al. 2008

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Down syndrome (DS) is one of the most frequent congenital birth defects, and the most common genetic cause of mental retardation. In most cases, DS results from the presence of an extra copy of chromosome 21. DS has a complex phenotype, and a major goal of DS research is to identify genotype -phenotype correlations. Cases of partial trisomy 21 and other HSA21 rearrangements associated with DS features could identify genomic regions associated with specific phenotypes. We have developed a BAC array spanning HSA21q and used array comparative genome hybridization (aCGH) to enable high-resolution mapping of pathogenic partial aneuploidies and unbalanced translocations involving HSA21. We report the identification and mapping of 30 pathogenic chromosomal aberrations of HSA21 consisting of 19 partial trisomies and 11 partial monosomies for different segments of HSA21. The breakpoints have been mapped to within B85 kb. The majority of the breakpoints (26 of 30) for the partial aneuploidies map within a 10-Mb region. Our data argue against a single DS critical region. We identify susceptibility regions for 25 phenotypes for DS and 27 regions for monosomy 21. However, most of these regions are still broad, and more cases are needed to narrow down the phenotypic maps to a reasonable number of candidate genomic elements per phenotype.

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“…The successful application of direct cDNA selection for identifying genes from chromosome 21 has recently been reported (11)(12)(13). We have utilized exon amplification to isolate over 100 gene fragments from a 2.5 Mb region of chromosome 21 between loci CBR and ERG, which is present in three copies in common in many DS individuals with partial trisomy 21 (4,5,7,10). Localization of these gene fragments to a physical map of the region has imparted higher resolution to the physical map and contributes to integration with a transcript map.…”

Section: Introductionmentioning

confidence: 99%

“…Since the association of Down syndrome (DS) with trisomy for human chromosome 21 (1,2), the study of this common birth defect has progressed from cytogenetic analyses of patient chromosomes (3) through the molecular characterization of gene and sequence dosage in individuals with partial trisomy 21 (4)(5)(6)(7)(8)(9). The resulting genotype-phenotype correlations that have emerged define subregions of the chromosome that likely contain genes contributing to specific features of DS (5,10).…”

Section: Introductionmentioning

confidence: 99%

Localization of 102 exons to a 2.5 Mb region involved in Down syndrome

Lucente

Chen

Shea³

et al. 1995

Hum Mol Genet

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Critical role of the D21S55 region on chromosome 21 in the pathogenesis of Down syndrome.

Cited by 228 publications

References 31 publications

DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1

DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1

Genotype–phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21

Localization of 102 exons to a 2.5 Mb region involved in Down syndrome

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