Showing papers on "Chromosome 21 published in 1996"

Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome.

Abstract: To study the pathogenesis of central nervous system abnormalities in Down syndrome (DS), we have analyzed a new genetic model of DS, the partial trisomy 16 (Ts65Dn) mouse. Ts65Dn mice have an extra copy of the distal aspect of mouse chromosome 16, a segment homologous to human chromosome 21 that contains much of the genetic material responsible for the DS phenotype. Ts65Dn mice show developmental delay during the postnatal period as well as abnormal behaviors in both young and adult animals that may be analogous to mental retardation. Though the Ts65Dn brain is normal on gross examination, there is age-related degeneration of septohippocampal cholinergic neurons and astrocytic hypertrophy, markers of the Alzheimer disease pathology that is present in elderly DS individuals. These findings suggest that Ts65Dn mice may be used to study certain developmental and degenerative abnormalities in the DS brain.

Down's syndrome-like skeletal abnormalities in Ets2 transgenic mice.

Abstract: EXPRESSION of Ets2, a proto-oncogene1 and transcription factor2–5, occurs in a variety of cell types6. During murine development it is highly expressed in newly forming cartilage, including in the skull precursor cells and vertebral primordia7. Ets2 is located on human chromosome 21 (ref. 8) and is overexpressed in Down's syndrome (trisomy 21)9. Here we generate transgenic mice to investigate the consequences of overexpression of Ets2. We find that mice with less than 2-foldEts2 overexpression in particular organs develop neurocranial, viscerocranial and cervical skeletal abnormalities. These abnormalities have similarities with the skeletal anomalies found in trisomy-16 mice and humans with Down's syndrome, in which the gene dosage of Ets2 is increased10,12. Our results indicate that Ets2 has a role in skeletal development and implicate the overexpression of Ets2 in the genesis of some skeletal abnormalities that occur in Down's syndrome.

A Human Homologue of Drosophila Minibrain (Mnb) Is Expressed in the Neuronal Regions Affected in Down Syndrome and Maps to the Critical Region

Abstract: The minibrain (mnb) gene of Drosophila melanogaster encodes a serine-threonine protein kinase with an essential role in postembryonic neurogenesis. A corresponding human gene with similar function to mnb could provide important insights into both normal brain development and the abnormal brain development and mental retardation observed in many congenital disorders. Trisomy 21 or Down syndrome (DS) is the most frequent human birth defect. It is associated with mental retardation and a broad spectrum of physical abnormalities. A region on human chromosome 21 has been designated the Down syndrome critical region (DSCR) and when present in three copies, this is responsible for many of the characteristic features of DS, including mental retardation. We have isolated a human homologue of mnb from the DSCR. MNB encodes a 6.1 kb transcript which is expressed in foetal brain, lung, kidney and liver. Using a human probe, two major transcripts (6.1 and 3.1 kb) were identified in mouse and expression was detected in situ in several regions of the mouse brain, including the olfactory bulb, the cerebellum, the cerebral cortex, the pyramidal cell layer of the hippocampus and several hypothalamic nuclei. This expression pattern corresponds to the regions of the brain that are abnormal in individuals with DS and suggests that overexpression of MNB could have detrimental consequences in DS patients.

The AML1yETO fusion protein activates transcription of BCL-2

Abstract: The AML1 gene, located on chromosome 21, is involved in several distinct chromosomal translocations in human leukemia. In t(8;21) acute myelogenous leukemia (AML),theAML1geneisjuxtaposedtotheETOgenelocated on chromosome 8, generating an AML1yETO fusion protein. BothAML1yETOandtheAML1proteinsrecognizethesame consensus DNA-binding motif (TGTyCGGT), which is found in the promoters of several genes involved in hematopoiesis. Wefoundthattwomyeloidleukemiacelllineswiththet(8;21) translocation, Kasumi and SKNO-1, have elevated levels of BCL-2 protein compared with other myeloid cell lines. In addition, we identified a consensus AML1 binding site in the BCL-2 promoter. Thus far, AML1yETO has been shown to dominantly repress its target genes; however, we found that AML1yETOactivatestranscriptionoftheBCL-2geneinU937 cells. This activation requires the presence of both the runt homologydomain(rhd)andtheC-terminalportionofAML1y ETO. We demonstrated sequence specific binding of both AML1A and AML1yETO to the TGTGGT sequence in the BCL-2 promoter and showed that the AML1 binding site is required for responsiveness to AML1yETO. Interestingly, AML1AandAML1BdonotmodulatetheactivityoftheBCL-2 promoter. The elevated levels of BCL-2 in cells that express AML1yETOmayprolongtheirlifespanandcontributetothe development of t(8;21) leukemia.

Lack of chromosome territoriality in yeast: promiscuous rejoining of broken chromosome ends.

Abstract: Various studies suggest that eukaryotic chromosomes may occupy distinct territories within the nucleus and that chromosomes are tethered to a nuclear matrix. These constraints might limit interchromosomal interactions. We have used a molecular genetic test to investigate whether the chromosomes of Saccharomyces cerevisiae exhibit such territoriality. A chromosomal double-strand break (DSB) can be efficiently repaired by recombination between flanking homologous repeated sequences. We have constructed a strain in which DSBs are delivered simultaneously to both chromosome III and chromosome V by induction of the HO endonuclease. The arrangement of partially duplicated HIS4 and URA3 sequences around each HO recognition site allows the repair of the two DSBs in two alternative ways: (i) the creation of two intrachromosomal deletions or (ii) the formation of a pair of reciprocal translocations. We show that reciprocal translocations are formed approximately as often as the pair of intrachromosomal deletions. Similar results were obtained when one of the target regions was moved from chromosome V to any of three different locations on chromosome XI. These results argue that the broken ends of mitotic chromosomes are free to search the entire genome for appropriate partners; thus, mitotic chromosomes are not functionally confined to isolated domains of the nucleus, at least when chromosomes are broken.

Aneuploidy in human sperm: the use of multicolor FISH to test various theories of nondisjunction.

Abstract: While it is known that all chromosomes are susceptible to meiotic nondisjunction, it is not clear whether all chromosomes display the same frequency of nondisjunction. By use of multicolor FISH and chromosome-specific probes, the frequency of disomy in human sperm was determined for chromosomes 1, 2, 4, 9, 12, 15, 16, 18, 20, and 21, and the sex chromosomes. A minimum of 10,000 sperm nuclei were scored from each of five healthy, chromosomally normal donors for every chromosome studied, giving a total of 418,931 sperm nuclei. The mean frequencies of disomy obtained were 0.09% for chromosome 1; 0.08% for chromosome 2; 0.11% for chromosome 4; 0.14% for chromosome 9; 0.16% for chromosome 12; 0.11% for chromosomes 15, 16, and 18; 0.12% for chromosome 20; 0.29% for chromosome 21; and 0.43% for the sex chromosomes. Data for chromosomes 1, 12, 15, and 18, and the sex chromosomes have been published elsewhere. When the mean frequencies of disomy were compared, the sex chromosomes and chromosome 21 had significantly higher frequencies of disomy than that of any other autosome studied. These results corroborate the pooled data obtained from human sperm karyotypes and suggest that the sex chromosome bivalent and the chromosome 21 bivalent are more susceptible to nondisjunction during spermatogenesis. From these findings, theories proposed to explain the variable incidence of nondisjunction can be supported or discarded as improbable.

Autosomal Recessive Non-Syndromic Deafness Locus (DFNB8) Maps on Chromosome 21Q22 in a Large Consanguineous Kindred from Pakistan

Abstract: Autosomal recessive childhood-onset non-syndromic deafness is one of the most frequent forms of inherited hearing impairment. Recently five different chromosomal regions, 7q31, 11q13.5, 13q12, 14q and the pericentromeric region of chromosome 17, have been shown to harbour disease loci for this type of neurosensory deafness. We have studied a large family from Pakistan, containing several consanguineous marriages and segregating for a recessive non-syndromic childhood-onset deafness. Linkage analysis mapped the disease locus (DFNB8) on the distal long arm of chromosome 21, most likely between D21S212 and D21S1225 with the highest lod score of 7.31 at theta = 0.00 for D21S1575 on 21q22.3.

Incidence of chromosome 21 disomy in human spermatozoa as determined by fluorescent in-situ hybridization

Abstract: We have evaluated the incidence of chromosome 21 disomy in decondensed sperm heads from nine normal men using a locus-specific DNA probe for chromosome 21, and a centromeric probe for chromosome 6 as a control. The results show that the incidence of chromosome 21 disomy (0.38%) is significantly higher than disomy for chromosome 6 (0.14%). No differences were found among the individuals analysed.

Cloning of the cDNA for a human homologue of the Drosophila white gene and mapping to chromosome 21q22.3.

Abstract: In an effort to contribute to the transcript map of human chromosome 21 and the understanding of the pathophysiology of trisomy 21, we have used exon trapping to identify fragments of chromosome 21 genes. Two trapped exons, from pools of chromosome 21-specific cosmids, showed homology to the Drosophila white (w) gene. We subsequently cloned the corresponding cDNA for a human homologue of the Drosophila w gene (hW) from human retina and fetal brain cDNA libraries. The gene belongs to the ATP-binding cassette transporter gene family and is homologous to Drosophila w (and to w genes from other species) and to a lesser extent to Drosophila brown (bw) and scarlet (st) genes that are all involved in the transport of eye pigment precursor molecules. A DNA polymorphism with 62% heterozygosity due to variation of a poly (T) region in the 3' UTR of the hW has been identified and used for the incorporation of this gene to the genetic map of chromosome 21. The hW is located at 21q22.3 between DNA markers D21S212 and D21S49 in a P1 clone that also contains marker BCEI. The gene is expressed at various levels in many human tissues. The contributions of this gene to the Down syndrome phenotypes, to human eye color, and to the resulting phenotypes of null or missense mutations are presently unknown.

A Large Variety of Alternatively Spliced and Differentially Expressed mRNAs Are Encoded by the Human Acute Myeloid Leukemia Gene AML1

Abstract: The human chromosome 21 acute myeloid leukemia gene AML1 is frequently rearranged in the leukemia-associated translocations t(8;21) and t(3;21), generating fused proteins containing the am...

Linkage of congenital recessive deafness (gene DFNB10) to chromosome 21q22.3

Abstract: Deafness is a heterogeneous trait affecting approximately 1/1,000 newborns. Genetic linkage studies have already implicated more than a dozen distinct loci causing deafness. We conducted a genome search for linkage in a large Palestinian family segregating an autosomal recessive form of nonsyndromic deafness. Our results indicate that in this family the defective gene, DFNB10, is located in a 12-cM region near the telomere of chromosome 21. This genetic distance corresponds to or = to 3. Homozygosity of marker alleles was evident for only the most telomeric marker, D21S1259, suggesting that DFNB10 is closest to this locus. To our knowledge, this is the first evidence, at this location, for a gene that is involved in the development or maintenance of hearing. As candidate genes at these and other deafness loci are isolated and characterized, their roles in hearing will be revealed and may lead to development of mechanisms to prevent deafness.

Genes contributing to Alzheimer's disease.

Abstract: We propose that Alzheimer's disease (AD) is a single disease with a common metabolic APP-beta A4-amyloid pathway. The multiple genetic and other factors already identified to induce this pathway are reviewed. The molecular genetics of AD has been successfully studied within the last years, and we now can account for the genetic and molecular alterations underlying the majority of familial AD cases inherited with an autosomal dominant pattern of complete penetrance. AD in these pedigrees can be caused by missense mutations within the recently identified PS1 (S182) gene on chromosome 14 (AD3 locus) and the PS2 (STM2/E5-1) gene on chromosome 1, in addition to previously described point mutations of the beta A4-amyloid protein precursor (APP) gene on chromosome 21 (AD1 locus). The majority of AD cases, however, appears to be sporadic or 'familial' in terms of an increased family-associated AD-probability. Genetic risk factors contributing to AD in these cases have also been identified. On chromosome 19, allelic segregation of the APOE gene with both late onset 'familial' (AD2) and sporadic AD has been demonstrated, with the APOE epsilon 4 allele conferring a relatively higher risk of developing AD at an earlier age. Several other risk factors have also been proposed, including the alpha 1-antichymotrypsin allele A (ACT-A), the 5-repeat allele of the VLDL-receptor (VLDL-R) gene, the A2 allele of the HLA-A locus, and possibly yet unknown mitochondrial mutations. All these findings are discussed against the background of what is known about APP metabolism leading to beta A4 amyloid formation, a process that is also modified by APP expression level, alternative splicing of APP exon 15, extracellular signalling and intracellular sorting.

Molecular genetic basis of familial ALS

Abstract: Familial amytrophic lateral sclerosis (FALS) is transmitted in a mendelian fashion as an autosomal dominant (DFALS) or an autosomal recessive (RFALS) trait.Both DFALS and RFALS are genetically heterogeneous. Fifteen percent of DFALS families have mutations in the gene for Cu, Zn superoxide dismutase (SOD1) which is coded on chromosome 21. The locus for one form of RFALS maps to chromosome 2q33. Forty-six mutations in the SOD1 gene have been reported in DFALS families. These mutations result in decreased SOD1 activity and shortened half-life of the protein in most instances. Transgenic mice overexpressing mutated SOD1 protein develop an ALS-like disease which suggests that the degeneration of motor neurons in DFALS is caused by the gain of a novel toxic function by mutated SOD1 rather than by the decrease of SOD1 activity. Several possible mechanisms of the novel neurotoxic function of mutated SOD1 are discussed. NEUROLOGY 1996;47(Suppl 2): S27-S35

Dosage compensation regulatory proteins and the evolution of sex chromosomes in Drosophila.

Abstract: In the fruitfly Drosophila melanogaster, the four male specific lethal (msl) genes are required to achieve dosage compensation of the male X chromosome. The MSL proteins are thought to interact with cis-acting sites that confer dosage compensation to nearby genes, as they are detected at hundreds of discrete sites along the length of the polytene X chromosome in males but not in females. The histone H4 acetylated isoform, H4Ac16, colocalizes with the MSL proteins at a majority of sites on the D. melanogaster X chromosome. Using polytene chromosome immunostaining of other species from the genus Drosophila, we found that X chromosome association of MSL proteins and H4Ac16 is conserved despite differences in the sex chromosome karyotype between species. Our results support a model in which cis-acting regulatory sites for dosage compensation evolve on a neo-X chromosome arm in response to the degeneration of its former homologue.

Down syndrome genetics : unravelling a multifactorial disorder

Abstract: Down syndrome is a common disorder affecting many tissues both during development and later on in adult life; the principle feature of all cases is a specific form of mental retardation, which is combined with a range of variable traits. Down syndrome is an aneuploidy syndrome that is caused by trisomy for human chromosome 21. While the phenotype is most likely due to a subtle increase in gene dosage of only a small minority of the estimated 500-800 genes that are present on this chromosome, the molecular genetics of Down syndrome remains speculative. However, recent advances on a number of fronts, including chromosome studies, gene identification and mouse modelling, are giving us the tools to dissect this multifactorial gene dosage disorder.

Multiple regions of chromosome 6q affected by loss of heterozygosity in primary human breast carcinomas.

Abstract: A total of 80 primary human breast carcinoma DNAs were analysed for loss of heterozygosity (LOH) on the long arm of chromosome 6, using microsatellite markers whose location has been defined physically and by linkage analysis. Loss of heterozygosity was observed in 38 of 80 (48%) tumours that were informative for at least one locus. The analysis revealed partial or interstitial deletions of chromosome 6q. Detailed mapping of chromosome 6q in these tumour DNAs identified two and perhaps three commonly deleted regions. One of these is located between markers D6S251 and D6S252 (6q14-q16.2), another between D6S268 and D6S261 (6q16.3-q23) and a third between D6S287 and D6S270 (6q22.3-q23.1).

Chromosome painting defines genomic rearrangements between red howler monkey subspecies

Abstract: We hybridized whole human chromosome-specific DNA libraries to chromosomes of two supposed subspecies ofAlouatta seniculus: Alouatta seniculus sara andAlouatta seniculus arctoidea. The number of hybridization signals per haploid set is 42 inA. s. sara and 43 inA. s. arctoidea; the two karyotypes differ by at least 16 chromosomal rearrangements, including numerous translocations. An unusual sex chromosome system is shared by both taxa. The sex chromosome system results from a Y translocation with a chromosome homologous to parts of human chromosome 3/15 and can be described as X1X2Y1Y2/X1X1X2X2 (male/female). Both red howlers also have microchromosomes, a highly unusual karyological trait not found in other higher primates. These microchromosomes are not hybridized by any human chromosome paint and therefore are probably composed of repetitive DNA. It is well known that New World monkeys have high karyological variability. It is probable that molecular cytogenetic analyses including chromosome painting will permit an accurate reconstruction of the phylogeny of these monkeys and help establish the ancestral karyotype for higher primates.

Recognition of homeology by the wheat Ph1 locus.

Abstract: Chromosome 1A(m) of Triticum monococcum is closely homeologous to T. aestivum chromosome 1A but recombines with it little in the presence of the wheat suppressor of homeologous chromosome pairing, Ph1. In the absence of Ph1, the two chromosomes recombine as if they were completely homologous. Chromosomes having either terminal or interstitial segments of chromosome 1A(m) in 1A were constructed and their recombination with 1A was investigated in the presence of Ph1. No recombination was detected in the homeologous (1A(m)/1A) segments, irrespective of whether terminally or interstitially positioned in a chromosome, whereas the levels of recombination in the juxtaposed homologous (1A/1A) segments was normal or close to normal relative to completely homologous 1A chromosomes. These observations show that Ph1 does not regulate chromosome pairing by premeiotic chromosome alignment and a mitotic spindle-centromere interaction, as has been suggested, but processes homology along the entire length of chromosomes.

Development of a bovine X chromosome linkage group and painting probes to assess cattle, sheep, and goat X chromosome segment homologies

Abstract: The X chromosome linkage group is conserved in placental mammals. However, X chromosome morphological differences, due to internal chromosome rearrangements, exist among mammalian species. We have developed bovine chromosome painting probes for Xp and Xq to assess segment homologies between the submetacentric bovine X chromosome and the acrocentric sheep and goat X chromosomes. These painting probes and their corresponding DNA libraries were developed by chromosome micromanipulation, DNA micropurification, microcloning, and PCR amplification. The bovine Xp painting probe identified an interstitially located homologous segment in the sheep and goat Xq region, most probably resulting from chromosome inversion. Ten type II (microsatellite) markers obtained from the bovine Xq library and five other X chromosome assigned, but unlinked, markers were used to generate a linkage map for Xq spanning 89.4 centimorgans. The chromosome painting probes and molecular markers generated in this study would be useful for comparative mapping and tracing of internal X chromosome rearrangements in all ruminant species and would contribute to the understanding of mammalian sex chromosome evolution.

Overexpression of copper-zinc superoxide dismutase in trisomy 21.

Abstract: Down's syndrome (DS), the most frequent of congenital birth defects, results from the trisomy of chromosome 21 in all cells of affected patients. This disease is characterized by developmental anomalies, mental retardation and features of rapid aging, particularly in the brain, where the occurrence of Alzheimer's disease is observed in trisomy 21 patients over the age of 35. Copper-zinc superoxide dismutase (CuZnSOD) is one of the proteins encoded by chromosome 21 (21q22.1). As a consequence of gene dosage excess, CuZnSOD activity is increased by 50% in all DS tissues. This work reports the SOD activity of a population of DS patients with complete trisomy 21, partial trisomy 21, translocations and mosaicism, in order to confirm the gene dosage effect of SOD on the clinical features of DS, and to help to establish which is the critical region of chromosome 21 in DS. CuZnSOD was measured in red blood cells using the Minami and Yoshikawa method. In the population with complete trisomy 21, SOD activity was increased by 42%; in the population with partial trisomy 21, translocations and mosaicism, SOD activity was normal. In the population diagnosed as DS, but not karyotyped, SOD activity was increased by 28%. No differences between sexes or among ages were found. We conclude that the 21q22.1 segment is not the critical region responsible for DS, as we have found normal SOD activity in patients with the clinical features of DS.

Molecular evolution of the Sex-Ratio inversion complex in Drosophila pseudoobscura: analysis of the Esterase-5 gene region.

Abstract: The Sex-Ratio chromosome in Drosophila pseudoobscuru is subject to meiotic drive. It is associated with a series of three nonoverlapping paracentric inversions on the right arm of the X chromosome. The ester-use-5 gene region has been localized to section 23 within the subbasal inversion of the Sex-Ratio inversion complex, making esteruse5 a convenient locus for molecular evolutionary analyses of the Sex-Ratio inversion complex and the associated drive system. A 504-bp fragment of noncoding, intergenic DNA from the esteruse- gene region was amplified and sequenced from 14 Sex-Ratio and 14 Standard X chromosomes of D. pseudoobscuru, and from 9 X chromosomes of its two sibling species, Drosophila persimilis and Drosophila mirundu. There is extensive sequence differentiation between the Sex-Ratio and Standard chromosomal types. The common Standard chromosome is highly polymorphic, while, as expected from either the neutral mutation theory or the selective sweep hypothesis, the rarer Sex-Ratio chromosome has much less within-chromosome nucleotide polymorphism. We estimate that the Standard and SexRatio chromosomes in D. pseudoobscuru diverged between 700,000 and 1.3 Mya, or at least 2 million generations ago. The clustering of D. pseudoobscuru Sex-Ratio chromosomes in a neighbor-joining phylogeny indicates a fairly old, monophyletic origin in this species. It appears from these data that Sex-Ratio genes were present prior to the divergence of D. pseudoobscuru and D. persimilis and that both the Standard and Sex-Ratio chromosomes of D. persimilis were derived from the Standard chromosome of D. pseudoobscuru after the inversion events that isolated

Consequences of Trisomy 16 for Mouse Brain Development: Corticogenesis in a Model of Down Syndrome

Abstract: We have studied abnormalities in the tangential and radial expansion of the cerebral cortex during fetal development in the trisomy 16 (Ts16) mouse, a model for human trisomy 21 (Down syndrome). Slowed tangential expansion of the neuroepithelium in Ts16 resulted in a reduction of final telencephalic size and is predicted to decrease the number of radial cortical units in the mature brain. In addition, radial growth of the Ts16 cortex was delayed at the time of peak cortical neurogenesis in normal mice, but by embryonic day 18 the cortex reached normal thickness. Because mouse chromosome 16 shares many genes with human chromosome 21, abnormalities in Ts16 brain development may parallel abnormalities in trisomy 21.