Down Syndrome Region Of Chromosome Research Articles

Prenatal diagnosis of trisomy 21 without the Down syndrome phenotype

To report a patient with the prenatal diagnosis of trisomy 21 without the clinical Down syndrome (DS) phenotype secondary to the absence of the Down syndrome chromosomal region (DSCR) in a derivative chromosome 21. A newborn patient with prenatal diagnosis of duodenal atresia. Cytogenetic studies revealed a regular trisomy 21. At birth, she did not present the clinical features of DS. FISH analysis was performed in the patient with the LSI spectrum probe for the DSCR and in the mother with FISH multicolor analysis using painting probes for chromosomes 20 and 21. FISH analysis in the patient showed two hybridization signals suggesting that the third chromosome 21 did not have the DSCR region explaining the absence of the DS phenotype. FISH multicolor analysis in the mother showed three hybridization signals for chromosomes 20 and 21, concluding a maternal karyotype, 46,XX,t(20;21)(p11.2;q22.1). The patient was found to have a derivative chromosome 21 secondary to a nondisjunction error in meiosis II without the DS critical region and the phenotype was mostly secondary to the combination of the two partial trisomies.

The Down Syndrome Cell Adhesion Molecule (DSCAM) Interacts with and Activates Pak

The Down syndrome cell adhesion molecule (DSCAM) is a member of the immunoglobulin superfamily that maps to a Down syndrome region of chromosome 21q22.2-22.3. In Drosophila, Dscam functions as an axon guidance receptor regulating targeting and branching. Genetic and biochemical studies have shown that in Drosophila, Dscam activates Pak1 via the Dock adaptor molecule. The extracellular domain of human DSCAM is highly homologous to the Drosophila protein; however, the intracellular domains of both human and Drosophila DSCAM share no obvious sequence identity. To study the signaling mechanisms of human DSCAM, we investigated the interaction between DSCAM and potential downstream molecules. We found that DSCAM directly binds to Pak1 and stimulates Pak1 phosphorylation and activity, unlike Drosophila where an adaptor protein Dock mediates the interaction between Dscam and Pak1. We also observed that DSCAM activates both JNK and p38 MAP kinases. Furthermore, expression of the cytoplasmic domain of DSCAM induces a morphological change in cultured cells that is JNK-dependent. These observations suggest that human DSCAM also signals through Pak1 and may function in axon guidance similar to the Drosophila Dscam.

β-Secretase revealed: starting gate for race to novel therapies for Alzheimer’s disease

Although remarkable progress has been made in the identification of BACE as β-secretase, there is still much to be done. For example, although BACE-mediated cleavage of APP might be important to the pathogenesis of AD, its role in normal cellular function remains unknown. This issue could be addressed by analysing transgenic mice that overexpress BACE, as well as mice that are deficient in both copies of the gene that encodes BACE. It will also be important to understand how BACE activity is regulated in the cell and how this regulation affects APP processing and Aβ production. For example, we already know that overexpression of BACE leads to decreased processing of APP by the alternative α-secretase pathway10xβ-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Vassar, R. et al. Science. 1999; 286: 735–741Crossref | PubMed | Scopus (2413)See all References10. Similarly, protein kinase C (PKC)-mediated stimulation of α-secretase results in decreased β-secretase processing of APP, which suggests that these two enzymes might compete for cleavage of APP (Ref. 23xProtein kinase C-dependent α-secretase competes with β-secretase for cleavage of amyloid-β precursor protein in the trans-Golgi network. Skovronsky, D.M. et al. J. Biol. Chem. 2000; 275: 2568–2578Crossref | PubMed | Scopus (243)See all ReferencesRef. 23). Whether dysregulation of β-secretase or α-secretase contributes to the pathogenesis of AD has yet to be tested.It is tempting to speculate that polymorphisms in the BACE gene that affect BACE function might be linked to altered risks of AD. However, the BACE gene, which has been mapped to chromosome 11 (2xA pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of β-amyloid. Mullan, M. et al. Nat. Genet. 1992; 1: 345–347Crossref | PubMed | Scopus (813)See all References, 12xMembrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity. Yan, R. et al. Nature. 1999; 402: 533–537Crossref | PubMed | Scopus (1098)See all References), has not yet been associated genetically with AD. Interestingly, the BACE2 gene, like the gene encoding APP, maps to the obligate Down syndrome region of chromosome 21 (12xMembrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity. Yan, R. et al. Nature. 1999; 402: 533–537Crossref | PubMed | Scopus (1098)See all References, 22xBACE maps to chromosome 11 and a BACE homolog, BACE2, reside in the obligate down syndrome region of chromosome 21. Saunders, A.J. et al. Science. 1999; 286: 1255aCrossrefSee all References), and Down syndrome patients invariably develop amyloid plaques and AD-like pathology.Finally, the discovery of BACE as β-secretase greatly facilitates the prospects for the development of potential AD therapeutics. With a target protease now in hand, it will be possible to generate small-molecule inhibitors of BACE that could reduce Aβ production. On the basis of the success of protease inhibitors to retard progression of AIDS, the future propects for protease inhibition therapy for AD appear bright. Clinical trials of such BACE inhibitors will provide valuable clues to the pathogenesis of AD. By inhibiting Aβ production and senile plaque formation, these drugs will enable us to examine the link between senile plaques and dementia, thus providing the means for testing the amyloid cascade hypothesis in vivo.

BACE2, a Homolog of BACE, in the Down Syndrome Region of Chromosome 21

BACE2, a Homolog of BACE, in the Down Syndrome Region of Chromosome 21

Expression of the transcription factor ETS2 in brain of patients with Down syndrome--evidence against the overexpression-gene dosage hypothesis.

Overexpression of the transcription factor ETS2 and other genes localized in the socalled critical Down Syndrome region of chromosome 21 due to a gene dosage effect, is an attractive hypothesis for the explanation of the Down Syndrome phenotype. The overexpression of ETS2, however, has never been demonstrated in a human organ. We therefore challenged this hypothesis determining ETS2 levels in several brain regions of patients with Down Syndrome as compared to controls. We used a highly sensitive and quantitative RT-PCR method for the determination of ETS2 mRNA steady state levels in frontal, parietal, temporal, occipital lobe and cerebellum of 9 adult Down Syndrome patients and 9 adult controls. Significantly decreased ETS2 mRNA steady state levels (16.9 +/- 26.7 attogram mRNA ETS2/10 ng total RNA versus 87.7 +/- 92.9 in controls) in frontal lobe of Down Syndrome brain and decreased ETS2 mRNA steady state levels (6.99 +/- 6.4 attogram mRNA ETS2/100 pg beta-actin versus 19.8 +/- 15.7 in controls) in temporal lobe of Down Syndrome brain were found. In the other brain regions no statistically significant difference was detected. Our data provide evidence against the overexpression hypothesis for the development of the Down Syndrome phenotype. Decreased ETS2 transcripts found in temporal and frontal lobe of patients with Down Syndrome, however, may be involved in the pathogenesis of Down Syndrome including specific neurodegenerative processes and deteriorated plasticity of the brain taking place in Down Syndrome brain, as the concerted action of transcription factors may be seriously impaired.

Identification and Characterization of a New Human Gene Encoding a Small Protein with High Homology to the Proline-Rich Region of the SH3BGR Gene

As part of an effort to identify genes potentially involved in the Down Syndrome pathogenesis, in this paper we report the identification and characterization of a new human gene (named SH3BGRL), which shows a high homology to the SH3BGR gene, previously mapped to the Down Syndrome region of chromosome 21. The SH3BGRL gene encodes for a small protein of 114 amino acids, sharing 60% identity and 84% conservation on the amino acid level with the middle, proline-rich region of the SH3BGR gene and containing a similar SH3 (Scr homology 3) binding motif. The SH3BGRL and the proline-rich region of SH3BGR proteins appear to be highly conserved, sharing 95 and 98% identity, respectively, with the mouse homologues. A 1.9 kb transcript of the SH3BGRL gene has been found in all the tissues examined, in contrast with the expression pattern of the SH3BGR gene which is transcribed only in heart and skeletal muscle. The SH3BGR gene and its homologue, SH3BGRL, could be members of a new family of genes containing a highly conserved proline-rich functional domain. The SH3BGRL gene has been mapped by fluorescent in situ hybridization to Chromosome Xq13.3.

Interferon Action and Chromosome 21 Trisomy (Down Syndrome): 15 Years Later

A hypothesis relating interferon action and the chromosome 21 trisomy genotype and phenotype was presented in this journal in 1980. Since that time a number of additional genes involved in interferon action have been mapped to the distal Down Syndrome region of chromosome 21 and a growing literature has documented highly relevant pleiotropic effects of interferon in the brain. Thus, interferon continues to provide a potential basis for the phenotypic anomalies seen in the interferon supersensitive Down Syndrome patient. Further, the hypothesis that ribosomal RNA gene “satellite association” induced by interferon action is involved in the induction of chromosome 21 misdistribution at meiosis, is supported by extension of the cyclic correlation of Down Syndrome prevalence and virus epidemics, first observed by Stoller & Collmann in Australia from 1942 to 1964, to incidence data gathered by the CDC in the U.S. from 1968 to 1992. In addition, data from spontaneous abortuses and gametes assembled from the literature argue for a uniquely high frequency of chromosome 21 hyperploidy which suggests that the genes present on chromosome 21 play a role in its frequent misdistribution at meiosis. Taken together, these observations provide continued support for the hypothesis presented in 1980 that interferon action could be involved in the induction of both the trisomy 21 genotype and its resultant phenotype.

Mapping of the Gene for the p60 Subunit of the Human Chromatin Assembly Factor (CAF1A) to the Down Syndrome Region of Chromosome 21

Exon trapping was used to clone portions of genes from the Down syndrome critical region (DSCR) of human chromosome 21. One trapped sequence showed complete homology with nucleotide sequence U20980 (GenBank), which corresponds to the gene for the p60 subunit of the human chromatin assembly factor-1 (CAF1A). We mapped this gene to human chromosome 21 by fluorescencein situhybridization, by the use of somatic cell hybrids, and by hybridization to chromosome 21-specific YACs and cosmids. The CAF1A gene localizes to YACs 745H11 and 230E8 of the Chumakovet al.(1992,Nature359: 380) YAC contig, within the DSCR on 21q22. This CAF1A, which belongs to the WD-motif family of genes and interacts with other polypeptide subunits to promote assembly of histones to replicating DNA, may contribute in a gene dosage-dependent manner to the phenotype of Down syndrome.

Identification of a novel human gene containing the tetratricopeptide repeat domain from the Down syndrome region of chromosome 21.

The Down syndrome (DS) region on chromosome 21, which is responsible for the DS main features, has been defined by analysis of DS patients with partial trisomy 21. Within the DS region, we constructed a 1.6-Mb P1 contig map previously. To isolate gene fragments from the 1.6-Mb region, we performed direct cDNA library screening and exon trapping using the P1 clones and a human fetal brain cDNA library, and obtained 67 cDNA fragments and 52 possible exons. Among them, 23 cDNA fragments and 4 exons were interpreted to be derived from a single gene by localization on P1 clones and by Northern analysis. To obtain the full-length cDNA sequence, longer cDNA clones were further screened from another human cDNA library which was enriched with longer cDNA species. These clones were sequenced and assembled to a sequence of 9045 bp. This transcribed sequence encodes a novel 2025 amino-acid protein containing tetratricopeptide repeat (TPR) motifs and therefore the gene was designated as TPRD (a gene containing the TPR motifs on the Down syndrome region). The TPR domain has been found in a certain protein phosphatase and in other proteins involved in the regulation of RNA synthesis or mitosis. The TPRD gene, the novel gene which was proved to be in the 1.6-Mb region and to have the interesting features described above, is a candidate for genes responsible for the DS phenotypes.

Reverse Transcription-Polymerase Chain Reaction Detection of Transcribed Sequences on Human Chromosome 21

Seventy-four pairs of oligonucleotides derived from sequence-tagged sites (STSs) on the long arm of human chromosome 21, specifically from bands 21q22.1 to 21q22.3, were used in reverse transcription-polymerase chain reactions (RT-PCR) to detect the presence of expressed sequences in a fetal brain. These STSs included 69 that had not been related to transcribed sequences and 5 that had detected two known genes and three previously isolated cDNA clones. Of the 69 STSs analyzed in RT-PCR, 25 allowed amplification of specific cDNA fragments. The sizes of amplified cDNA fragments match those amplified from either human genomic DNA or somatic hybrid cells containing human chromosome 21. Of the 11 cDNA analyzed in Northern blot hybridizations, 6 hybridized to specific RNA species. The rapid screening for cDNA using previously mapped STSs has provided insight into the distribution of expressed sequences in this region of chromosome 21. Northern blot analysis of the amplified cDNA fragments has revealed interesting candidate genes in two disease loci. The marker D21S267 was previously mapped in the Down syndrome region of chromosome 21, and the marker D21S113 is closely linked to progressive myoclonus epilepsy. The cDNA fragments amplified using the primer sequences derived from D21S267 and D21S113 hybridized to 7- and 6.5-kb transcripts, respectively, which seem to express predominantly in brain.

3.6-Mb Genomic and YAC Physical Map of the Down Syndrome Chromosome Region on Chromosome 21

The Down syndrome chromosome region (DCR) on chromosome 21 has been shown to contain a gene(s) important in the pathogenesis of Down syndrome. We constructed a long-range restriction map of the D21S55-D21S65 region covering the proximal part of the DCR. Pulsed-field gel electrophoresis of lymphocyte DNA digested with three rare cutting enzymes. NotI, NruI, and MluI, was used to establish two physical linkage groups of 5 and 7 markers, respectively, spanning 4.6 Mb on the NotI map. Mapping analysis of 40 YACs allowed the selection of 13 YACs covering 95% of the D21S55-D21S65 region and spanning 3.6 Mb. The restriction maps of these YACs and their positioning on the genomic map allowed 19 markers to be ordered, including 4 NotI linking clones, 9 polymorphic markers, the CBR gene, and the AML1 gene. The distances between markers could also be estimated. This physical map and the location of eight NotI sites between D21S55 and D21S17 should facilitate the isolation of previously unidentified genes in this region.

Molecular Mapping of Twenty-Four Features of Down Syndrome on Chromosome 21

To determine which regions of chromosome 21 are involved in the pathogenesis of specific features of Down syndrome, we analysed, phenotypically and molecularly, 10 patients with partial trisomy 21. Six minimal regions for 24 features were defined by genotype-phenotype correlations. Nineteen of these features could be assigned to just 2 regions: short stature, joint hyperlaxity, hypotonia, major contribution to mental retardation and 9 anomalies of the face, hand and foot to the region D21S55, or Down syndrome chromosome region (DCR), located on q22.2 or very proximal q22.3, and spanning 0.4-3 Mb; 6 facial and dermatoglyphic anomalies to the region D21S55-MX1, including the DCR and spanning a maximum of 6 Mb on q22.2 and part of q22.3. Thus, the complex phenotype that constitutes Down syndrome may in large part simply result from the overdosage of only one or a few genes within the DCR and/or region D21S55-MX1.

Genetic mapping of the murine gene and 14 related sequences encoding chromosomal protein HMG-14.

The high-mobility-group chromosomal protein HMG-14 preferentially binds to nucleosomal core particles of mammalian chromatin and may modulate the chromatin configuration of transcriptionally active genes. The human gene for HMG-14 has been localized to the Down syndrome region of Chromosome (Chr) 21 and may be involved in the etiology of this syndrome. Here we show, by means of genetic linkage analysis of interspecific and intersubspecific backcross mice, that the murine functional gene, Hmg14, is located on the distal end of mouse Chr 16, a region known to have conserved synteny with human Chr 21. In addition to the functional gene for HMG-14, both human and mouse genomes contain many related sequences that are probably processed pseudogenes. Here we map the locations of 14 Hmg14-related sequences in two mouse genomes. The 14 mapped loci are widely dispersed on ten chromosomes (Chrs 3, 5, 7, 9, 11, 12, 16, 17, 19, and X) and can be detected efficiently with a single cDNA probe. Thus, the Hmg14 multigene family is well suited to serve as genetic markers for other linkage studies in mice.

Electrophysiological analysis of cultured fetal mouse dorsal root ganglion neurons transgenic for human superoxide dismutase-1 a gene in the Down syndrome region of chromosome 21

Our recent whole cell patch-pipette studies have shown that human trisomy 21 (Down syndrome) cultured fetal dorsal root ganglion (DRG) neurons have accelerated rates of action potential depolarization and repolarization, with reduced spike duration, compared to control neurons. Similar observations were made using DRG neurons from the trisomy 16 mouse, an animal model of trisomy 21. In this study we have used transgenic mice in order to investigate the relationship between excess gene dosage and neurophysiological abnormalities. DRG neurons which possessed additional copies of the gene for human superoxide dismutase-1 (SOD), a gene from the Down syndrome region of chromosome 21, were compared to normal neurons. No electrophysiological differences were found between the two groups of neurons, indicating that increased dosage of the SOD gene alone is not causal to action potential dysfunction found in trisomy 21 and trisomy 16 neurons.

Correction: Mapping of the Gene Encoding the -amyloid Precursor Protein and its Relationship to the Down Syndrome Region of Chromosome 21

Correction: Mapping of the Gene Encoding the -amyloid Precursor Protein and its Relationship to the Down Syndrome Region of Chromosome 21

Mapping of the gene encoding the β-amyloid precursor protein and its relationship to the Down syndrome region of chromosome 21

Mapping of the gene encoding the β-amyloid precursor protein and its relationship to the Down syndrome region of chromosome 21

Mapping of the gene encoding the beta-amyloid precursor protein and its relationship to the Down syndrome region of chromosome 21.

The gene encoding the beta-amyloid precursor protein has been assigned to human chromosome 21, as has a gene responsible for at least some cases of familial Alzheimer disease. Linkage studies strongly suggest that the beta-amyloid precursor protein and the product corresponding to familial Alzheimer disease are from two genes, or at least that several million base pairs of DNA separate the markers. The precise location of the beta-amyloid precursor protein gene on chromosome 21 has not yet been determined. Here we show, by using a somatic-cell/hybrid-cell mapping panel, in situ hybridization, and transverse-alternating-field electrophoresis, that the beta-amyloid precursor protein gene is located on chromosome 21 very near the 21q21/21q22 border and probably within the region of chromosome 21 that, when trisomic, results in Down syndrome.

Absence of duplication of chromosome 21 genes in familial and sporadic Alzheimer's disease.

The possibility that Alzheimer's disease (AD) is caused by overexpression or duplication of one or more genes on chromosome 21 has been raised by the observation of AD-like neuropathologic changes in individuals with Down syndrome and by the mapping of both the defect for familial AD and the amyloid beta protein gene to this autosome. Possible duplication on chromosome 21 was investigated in both familial and sporadic AD by means of restriction fragment length polymorphisms for the amyloid and SODI loci, as well as for DNA markers in the vicinity of the familial AD defect and in the critical Down syndrome region of chromosome 21. No evidence of increased DNA dosage was observed in either brain or leukocytes of patients with inherited or sporadic forms of AD. Duplication of these regions is therefore not a frequent event in either form of AD. Furthermore, no significant allelic association was detected between AD and any of the loci, including the amyloid and SODI genes, providing no support for the hypothesis that defects in these specific genes are the primary cause of AD.