Showing papers on "Chromosome 21 published in 2011"
TL;DR: Using a comparative genomic approach, this work has been able to locate precisely the translocation breakpoint in these two models and took advantage of this finding to derive a new and more efficient Ts65Dn genotyping strategy.
Abstract: Down syndrome (DS) is the most frequent genetic disorder leading to intellectual disabilities and is caused by three copies of human chromosome 21. Mouse models are widely used to better understand the physiopathology in DS or to test new therapeutic approaches. The older and the most widely used mouse models are the trisomic Ts65Dn and the Ts1Cje mice. They display deficits similar to those observed in DS people, such as those in behavior and cognition or in neuronal abnormalities. The Ts65Dn model is currently used for further therapeutic assessment of candidate drugs. In both models, the trisomy was induced by reciprocal chromosomal translocations that were not further characterized. Using a comparative genomic approach, we have been able to locate precisely the translocation breakpoint in these two models and we took advantage of this finding to derive a new and more efficient Ts65Dn genotyping strategy. Furthermore, we found that the translocations introduce additional aneuploidy in both models, with a monosomy of seven genes in the most telomeric part of mouse chromosome 12 in the Ts1Cje and a trisomy of 60 centromeric genes on mouse chromosome 17 in the Ts65Dn. Finally, we report here the overexpression of the newly found aneuploid genes in the Ts65Dn heart and we discuss their potential impact on the validity of the DS model.
181 citations
TL;DR: The world’s largest series of over 20,000 oocytes tested for aneuploidies, involving chromosomes 13,16, 18, 21 and 22, provides the data on the rates and types of aneuPLoidies and their origin, providing the first evidence for the differences in the aneuPloid embryo survival depending on the meiotic origin.
Abstract: This study presents the world’s largest series of over 20,000 oocytes tested for aneuploidies, involving chromosomes 13,16, 18, 21 and 22, providing the data on the rates and types of aneuploidies and their origin. Almost every second oocyte (46.8%) is abnormal, with predominance of extra chromatid errors predicting predominance of trisomies (53%) over monosomies (26%) in the resulting embryos (2:1), which is opposite to monosomy predominance observed in embryo testing. Of the detected anomalies in oocytes, 40% are complex, so testing for a few most prevalent chromosome errors may allow detection of the majority of abnormal embryos. Chromosome 21 and 22 errors are more prevalent, while two different patterns of error origin were observed for different chromosomes: chromosome 16 and 22 errors originate predominantly from meiosis II, compared with chromosome 13, 18 and 21 errors originating from meiosis I. This provides the first evidence for the differences in the aneuploid embryo survival depending on the meiotic origin. Considering the problem of mosaicism, which is the major limitation of the cleavage-stage testing, the direct oocyte aneuploidy testing by polar body analysis may be of obvious practical value in improving accuracy and reliability of avoiding aneuploid embryos for transfer.
152 citations
TL;DR: This approach identifies several hundred new sex-linked genes, and it is shown that this young Y chromosome retains many genes, yet these already have slightly reduced gene expression and are accumulating changes likely to reduce protein functions.
127 citations
TL;DR: A complex genetic interplay is revealed, showing that the diverse DS phenotypes are likely to be caused by increased copies of many genes, with individual genes contributing in different proportions to the variance in different aspects of the pathology.
Abstract: Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21) and results in a large number of phenotypes, including learning difficulties, cardiac defects, distinguishing facial features and leukaemia. These are likely to result from an increased dosage of one or more of the ∼310 genes present on Hsa21. The identification of these dosage-sensitive genes has become a major focus in DS research because it is essential for a full understanding of the molecular mechanisms underlying pathology, and might eventually lead to more effective therapy. The search for these dosage-sensitive genes is being carried out using both human and mouse genetics. Studies of humans with partial trisomy of Hsa21 have identified regions of this chromosome that contribute to different phenotypes. In addition, novel engineered mouse models are being used to map the location of dosage-sensitive genes, which, in a few cases, has led to the identification of individual genes that are causative for certain phenotypes. These studies have revealed a complex genetic interplay, showing that the diverse DS phenotypes are likely to be caused by increased copies of many genes, with individual genes contributing in different proportions to the variance in different aspects of the pathology.
120 citations
TL;DR: Compared transcript catalogs for Hsa21q, chimpanzee chromosome 21 (Ptr21q), and orthologous regions of mouse chromosomes 16, 17, and 10 for open reading frame (ORF) characteristics and conservation are compared.
Abstract: A comprehensive representation of the gene content of the long arm of human chromosome 21 (Hsa21q) remains of interest for the study of Down syndrome, its associated phenotypic features, and mouse models. Here we compare transcript catalogs for Hsa21q, chimpanzee chromosome 21 (Ptr21q), and orthologous regions of mouse chromosomes 16, 17, and 10 for open reading frame (ORF) characteristics and conservation. The Hsa21q and mouse catalogs contain 552 and 444 gene models, respectively, of which only 162 are highly conserved. Hsa21q transcripts were used to identify orthologous exons in Ptr21q and assemble 533 putative transcripts. Transcript catalogs for all three organisms are searchable for nucleotide and amino acid sequence features of ORF length, repeat content, experimental support, gene structure, and conservation. For human and mouse comparisons, three additional summaries are provided: (1) the chromosomal distribution of novel ORF transcripts versus potential functional RNAs, (2) the distribution of species-specific transcripts within Hsa21q and mouse models of Down syndrome, and (3) the organization of sense–antisense and putative sense–antisense structures defining potential regulatory mechanisms. Catalogs, summaries, and nucleotide and amino acid sequences of all composite transcripts are available and searchable at http://gfuncpathdb.ucdenver.edu/iddrc/chr21/home.php. These data sets provide comprehensive information useful for evaluation of candidate genes and mouse models of Down syndrome and for identification of potential functional RNA genes and novel regulatory mechanisms involving Hsa21q genes. These catalogs and search tools complement and extend information available from other gene annotation projects.
114 citations
TL;DR: This study refined a HAC vector without endogenous genes from human chromosome 21 in homologous recombination-proficient chicken DT40 cells, and demonstrated that any desired gene can be cloned into the HAC using the Cre-loxP system in Chinese hamster ovary cells, or a homologously recombination system inDT40 cells.
Abstract: Human artificial chromosomes (HACs) have several advantages as gene therapy vectors, including stable episomal maintenance, and the ability to carry large gene inserts. We previously developed HAC vectors from the normal human chromosomes using a chromosome engineering technique. However, endogenous genes were remained in these HACs, limiting their therapeutic applications. In this study, we refined a HAC vector without endogenous genes from human chromosome 21 in homologous recombination-proficient chicken DT40 cells. The HAC was physically characterized using a transformation-associated recombination (TAR) cloning strategy followed by sequencing of TAR-bacterial artificial chromosome clones. No endogenous genes were remained in the HAC. We demonstrated that any desired gene can be cloned into the HAC using the Cre-loxP system in Chinese hamster ovary cells, or a homologous recombination system in DT40 cells. The HAC can be efficiently transferred to other type of cells including mouse ES cells via microcell-mediated chromosome transfer. The transferred HAC was stably maintained in vitro and in vivo. Furthermore, tumor cells containing a HAC carrying the suicide gene, herpes simplex virus thymidine kinase (HSV-TK), were selectively killed by ganciclovir in vitro and in vivo. Thus, this novel HAC vector may be useful not only for gene and cell therapy, but also for animal transgenesis.
111 citations
TL;DR: The findings suggest that men with a moderately elevated aneuploidy rate may be at a higher risk of fathering paternally derived aneuPLoid pregnancies and among lifestyle factors, smoking, alcohol and caffeine have been studied extensively.
Abstract: We reviewed the frequency and distribution of disomy in spermatozoa obtained by multicolor-FISH analysis on decondensed sperm nuclei in (a) healthy men, (b) fathers of aneuploid offspring of paternal origin and (c) individuals with Klinefelter syndrome and XYY males. In series of healthy men, disomy per autosome is approximately 0.1% but may range from 0.03 (chromosome 8) to 0.47 (chromosome 22). The great majority of authors find that chromosome 21 (0.18%) and the sex chromosomes (0.27%) have significantly elevated frequencies of disomy although these findings are not universal. The total disomy in FISH studies is 2.26% and the estimated aneuploidy (2× disomy) is 4.5%, more than double that seen in sperm karyotypes (1.8%). Increased disomy levels of low orders of magnitude have been reported in spermatozoa of some normal men (stable variants) and in men who have fathered children with Down, Turner and Klinefelter syndromes. These findings suggest that men with a moderately elevated aneuploidy rate may be at a higher risk of fathering paternally derived aneuploid pregnancies. Among lifestyle factors, smoking, alcohol and caffeine have been studied extensively but the compounding effects of the 3 are difficult to separate because they are common lifestyle behaviors. Increases in sex chromosome abnormalities, some autosomal disomies, and in the number of diploid spermatozoa are general features in 47,XXY and 47,XYY males. Aneuploidy of the sex chromosomes is more frequent than aneuploidy of any of the autosomes not only in normal control individuals, but also in patients with sex chromosome abnormalities and fathers of paternally derived Klinefelter, Turner and Down syndromes.
103 citations
TL;DR: This study has provided evidence that chromosome 21 instability is the only anomaly among those so far investigated that is common to all iAMP21 patients, and therefore the initiating event is likely to be found among the complex structural rearrangements of this abnormal chromosome.
99 citations
TL;DR: The clinical features of myeloid leukemia in DS, recent research on the mechanisms of leukemogenesis, including the roles of GATA1 mutations and trisomy 21 are reviewed, and treatment strategies are discussed.
Abstract: Although adults with Down syndrome (DS) show a decreased incidence of cancer compared to individuals without DS, children with DS are at an increased risk of leukemia. Nearly half of these childhood leukemias are classified as acute megakaryoblastic leukemia (AMKL), a relatively rare subtype of acute myeloid leukemia (AML). Here, we summarize the clinical features of myeloid leukemia in DS, review recent research on the mechanisms of leukemogenesis, including the roles of GATA1 mutations and trisomy 21, and discuss treatment strategies. Given that trisomy 21 is a relatively common event in hematologic malignancies, greater knowledge of how the genes on chromosome 21 contribute to DS-AMKL will increase our understanding of a broader class of patients with leukemia.
84 citations
TL;DR: This work analyzes an ancient duplicated chromosome pair from grasses that has experienced very different evolution from all other such paleo-duplicated chromosome pairs and finds chromosome structural stratification, enrichment of autoimmune response–related genes and accelerated DNA rearrangement and gene loss that are reminiscent of the sex chromosomes of other taxa.
Abstract: Whole genome duplication ~70 million years ago provided raw material for Poaceae (grass) diversification. Comparison of rice (Oryza sativa), sorghum (Sorghum bicolor), maize (Zea mays), and Brachypodium distachyon genomes revealed that one paleo-duplicated chromosome pair has experienced very different evolution than all the others. For tens of millions of years, the two chromosomes have experienced illegitimate recombination that has been temporally restricted in a stepwise manner, producing structural stratification in the chromosomes. These strata formed independently in different grass lineages, with their similarities (low sequence divergence between paleo-duplicated genes) preserved in parallel for millions of years since the divergence of these lineages. The pericentromeric region of this homeologous chromosome pair accounts for two-thirds of the gene content differences between the modern chromosomes. Both intriguing and perplexing is a distal chromosomal region with the greatest DNA similarity between surviving duplicated genes but also with the highest concentration of lineage-specific gene pairs found anywhere in these genomes and with a significantly elevated gene evolutionary rate. Intragenomic similarity near this chromosomal terminus may be important in hom(e)ologous chromosome pairing. Chromosome structural stratification, together with enrichment of autoimmune response–related (nucleotide binding site–leucine-rich repeat) genes and accelerated DNA rearrangement and gene loss, confer a striking resemblance of this grass chromosome pair to the sex chromosomes of other taxa.
82 citations
TL;DR: The success in defining a cooperative interaction between DSCAM and COL6A2 suggests that the multi-tiered genetic approach taken involving human mapping data, comprehensive combinatorial screening in Drosophila, and validation in vivo in mice and in mammalian cells lines should be applicable to identifying specific loci mediating a broad variety of other polygenic disorders.
Abstract: A significant current challenge in human genetics is the identification of interacting genetic loci mediating complex polygenic disorders. One of the best characterized polygenic diseases is Down syndrome (DS), which results from an extra copy of part or all of chromosome 21. A short interval near the distal tip of chromosome 21 contributes to congenital heart defects (CHD), and a variety of indirect genetic evidence suggests that multiple candidate genes in this region may contribute to this phenotype. We devised a tiered genetic approach to identify interacting CHD candidate genes. We first used the well vetted Drosophila heart as an assay to identify interacting CHD candidate genes by expressing them alone and in all possible pairwise combinations and testing for effects on rhythmicity or heart failure following stress. This comprehensive analysis identified DSCAM and COL6A2 as the most strongly interacting pair of genes. We then over-expressed these two genes alone or in combination in the mouse heart. While over-expression of either gene alone did not affect viability and had little or no effect on heart physiology or morphology, co-expression of the two genes resulted in ≈50% mortality and severe physiological and morphological defects, including atrial septal defects and cardiac hypertrophy. Cooperative interactions between DSCAM and COL6A2 were also observed in the H9C2 cardiac cell line and transcriptional analysis of this interaction points to genes involved in adhesion and cardiac hypertrophy. Our success in defining a cooperative interaction between DSCAM and COL6A2 suggests that the multi-tiered genetic approach we have taken involving human mapping data, comprehensive combinatorial screening in Drosophila, and validation in vivo in mice and in mammalian cells lines should be applicable to identifying specific loci mediating a broad variety of other polygenic disorders.
TL;DR: Recent progress and future challenges in modeling DS-associated developmental cognitive disability in mice with an emphasis on hippocampus-related phenotypes are discussed.
Abstract: Down syndrome (DS) is mainly caused by the presence of an extra copy of human chromosome 21 (Hsa21) and is a leading genetic cause for developmental cognitive disabilities in humans. The mouse is a premier model organism for DS because the regions on Hsa21 are syntenically conserved with three regions in the mouse genome, which are located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. With the advance of chromosomal manipulation technologies, new mouse mutants have been generated to mimic DS at both the genotypic and phenotypic levels. Further mouse-based molecular genetic studies in the future may lead to the unraveling of the mechanisms underlying DS-associated developmental cognitive disabilities, which would lay the groundwork for developing effective treatments for this phenotypic manifestation. In this review, we will discuss recent progress and future challenges in modeling DS-associated developmental cognitive disability in mice with an emphasis on hippocampus-related phenotypes.
TL;DR: It is shown that early developmental refinement of visual circuits is perturbed in mouse models of Down syndrome and Dscam (Down syndrome cell adhesion molecule), a gene within the DSCR, is identified as a regulator of eye-specific segregation of retinogeniculate projections.
Abstract: Down syndrome (DS) is a developmental disorder caused by a third chromosome 21 in humans (Trisomy 21), leading to neurological deficits and cognitive impairment. Studies in mouse models of DS suggest that cognitive deficits in the adult are associated with deficits in synaptic learning and memory mechanisms, but it is unclear whether alterations in the early wiring and refinement of neuronal circuits contribute to these deficits. Here, we show that early developmental refinement of visual circuits is perturbed in mouse models of Down syndrome. Specifically, we find excessive eye-specific segregation of retinal axons in the dorsal lateral geniculate nucleus. Indeed, the degree of refinement scales with defects in the "Down syndrome critical region" (DSCR) in a dose-dependent manner. We further identify Dscam (Down syndrome cell adhesion molecule), a gene within the DSCR, as a regulator of eye-specific segregation of retinogeniculate projections. Although Dscam is not the sole gene in the DSCR contributing to enhanced refinement in trisomy, Dscam dosage clearly regulates cell spacing and dendritic fasciculation in a specific class of retinal ganglion cells. Thus, altered developmental refinement of visual circuits that occurs before sensory experience is likely to contribute to visual impairment in individuals with Down syndrome.
TL;DR: Although the authors could not identify any nucleotide alteration in DYRK1A and KCNJ6 in their cohort study for 150 patients with mental retardation with/without epilepsy, this study underscores the clinical importance of DSCR not only for DS but also for developmental disorders.
Abstract: A relatively small region of human chromosome 21 (Hsa21) is considered to play a major role in Down syndrome (DS) phenotypes, and the concept of a Down syndrome critical region (DSCR) has been proposed. The goal of the phenotype-genotype correlation study is to discover which genes are responsible for each DS phenotype. Loss of the genomic copy numbers of Hsa21 can give us important suggestion to understand the functions of the involved genes. Genomic copy number aberrations were analyzed by micro-array-based comparative genomic hybridization (aCGH) in 300 patients with developmental delay. Partial deletions of Hsa21 were identified in three patients with developmental delay, epilepsy, microcephaly, and distinctive manifestations. Two of the patients had mosaic deletions of 21q22-qter including a part of DSCR; one of whom whose mosaic ratio was higher than the other showed more severe brain morphogenic abnormality with colpocephaly, which was similar to the previously reported patients having pure deletions of 21q22-qter, indicating the critical region for cortical dysplasia at this region. The remaining patient had the smallest microdeletion with 480 kb in DSCR including DYRK1A and KCNJ6. Although we could not identify any nucleotide alteration in DYRK1A and KCNJ6 in our cohort study for 150 patients with mental retardation with/without epilepsy, this study underscores the clinical importance of DSCR not only for DS but also for developmental disorders. (C) 2010 Wiley-Liss, Inc.
TL;DR: The identification of molecular markers that are closely linked to gene(s) in Gossypium barbadense L. accession GB713 that confer a high level of resistance to reniform nematode (RN), Rotylenchulus reniformis Linford & Oliveira, would be very useful in cotton breeding programs.
Abstract: The identification of molecular markers that are closely linked to gene(s) in Gossypium barbadense L. accession GB713 that confer a high level of resistance to reniform nematode (RN), Rotylenchulus reniformis Linford & Oliveira, would be very useful in cotton breeding programs. Our objectives were to determine the inheritance of RN resistance in the accession GB713, to identify SSR markers linked with RN resistance QTLs, and to map these linked markers to specific chromosomes. We grew and scored plants for RN reproduction in the P1, P2, F1, F2, BC1P1, and BC1P2 generations from the cross of GB713 × Acala Nem-X. The generation means analysis using the six generations indicated that one or more genes were involved in the RN resistance of GB713. The interspecific F2 population of 300 plants was genotyped with SSR molecular markers that covered most of the chromosomes of Upland cotton (G. hirsutum L.). Results showed two QTLs on chromosome 21 and one QTL on chromosome 18. One QTL on chromosome 21 was at map position 168.6 (LOD 28.0) flanked by SSR markers, BNL 1551_162 and GH 132_199 at positions 154.2 and 177.3, respectively. A second QTL on chromosome 21 was at map position 182.7 (LOD 24.6) flanked by SSR markers BNL 4011_155 and BNL 3279_106 at positions 180.6 and 184.5, respectively. Our chromosome 21 map had 61 SSR markers covering 219 cM. One QTL with smaller genetic effects was localized to chromosome 18 at map position 39.6 (LOD 4.0) and flanked by SSR markers BNL 1721_178 and BNL 569_131 at positions 27.6 and 42.9, respectively. The two QTLs on chromosome 21 had significant additive and dominance effects, which were about equal for each QTL. The QTL on chromosome 18 showed larger additive than dominance effects. Following the precedent set by the naming of the G. longicalyx Hutchinson & Lee and G. aridum [(Rose & Standley) Skovsted] sources of resistance, we suggest the usage of Ren
barb1
and Ren
barb2
to designate these QTLs on chromosome 21 and Ren
barb3
on chromosome 18.
TL;DR: It is suggested that deletion of regions 1 and 2 is compatible with life and have a variable phenotype perhaps relating more to other genetic and environmental variables than to genes in the interval.
Abstract: Partial monosomy 21 was recently segregated into three regions associated with variable clinical severity. We describe 10 new patients, all examined by single nucleotide polymorphism (SNP) genotyping and G-banded karyotyping. Cohort A consisted of three patients seen in our medical genetics clinics with partial chromosome 21 monosomies. In two of these patients having terminal deletions (21q22.2-ter and 21q22.3-ter), the breakpoints differed by at least 812 Kb of sequence, containing seven RefSeq genes. A third patient had an interstitial hemizygous loss of 16.4 Mb (21q21.1–q22.11). All three patients had relatively mild phenotypes. Cohort B consisted of seven patients with partial chromosome 21 monosomies who had a greater number of dysmorphic features and some major malformations; SNP genotypes were obtained from the Coriell Genetic Cell Repository. We also collected data on partial monsomy 21 cases from the DECIPHER database. This report of 10 new cases of 21q deletion and review of a total of 36 confirms that deletion of the terminal region is associated with a mild phenotype, but suggests that deletion of regions 1 and 2 is compatible with life and have a variable phenotype perhaps relating more to other genetic and environmental variables than to genes in the interval.
TL;DR: The smallest critical genomic region for DS-associated heart defects is established to lay the foundation for identifying the causative gene(s) for this phenotype.
Abstract: Human trisomy 21, the chromosomal basis of Down syndrome (DS), is the most common genetic cause of heart defects. Regions on human chromosome 21 (Hsa21) are syntenically conserved with three regions located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. In this study, we have analyzed the impact of duplications of each syntenic region on cardiovascular development in mice and have found that only the duplication on Mmu16, i.e., Dp(16)1Yey, is associated with heart defects. Furthermore, we generated two novel mouse models carrying a 5.43-Mb duplication and a reciprocal deletion between Tiam1 and Kcnj6 using chromosome engineering, Dp(16Tiam1-Kcnj6)Yey/+ and Df(16Tiam1-Kcnj6)Yey/+, respectively, within the 22.9-Mb syntenic region on Mmu16. We found that Dp(16Tiam1-Kcnj6)Yey/+, but not Dp(16)1Yey/Df(16Tiam1-Kcnj6)Yey, resulted in heart defects, indicating that triplication of the Tiam1-Knj6 region is necessary and sufficient to cause DS-associated heart defects. Our transcriptional analysis of Dp(16Tiam1-Kcnj6)Yey/+ embryos confirmed elevated expression levels for the genes located in the Tiam-Kcnj6 region. Therefore, we established the smallest critical genomic region for DS-associated heart defects to lay the foundation for identifying the causative gene(s) for this phenotype.
TL;DR: The findings obtained suggest (i) intraspecific origin of B chromosome, and (ii) evolutionary enrichment of repetitive DNA classes, especially those contained in the Cot−1 and the As51 probes, in B chromosome.
Abstract: Chromosome painting (CP) with a probe of B chromosome obtained by microdissection and fluorescence in situ hybridization (FISH) with probes of As51 satellite DNA, C
o
t−1 DNA, and 18S and 5S rDNA confirmed sharing of some repetitive DNA but not rDNA between A and B chromosomes in the fish Astyanax scabripinnis. Meiotic analysis revealed a pachytene B chromosome bivalent nearly half the size of its mitotic configuration, suggesting a self-pairing of B chromosome arms. Such an isochromosome nature of somatic B chromosome was further evidenced by CP and FISH. All the findings obtained suggest (i) intraspecific origin of B chromosome, and (ii) evolutionary enrichment of repetitive DNA classes, especially those contained in the C
o
t−1 and the As51 probes, in B chromosome. However, the precise origin of B chromosome in the present species remains to be elucidated by further molecular cytogenetic analysis because of painting of some A chromosome regions with the B chromosome-derived probe.
TL;DR: A review of the known mutations in GATA-1, focusing on the specific alterations within the amino acid sequence, the resulting effect on hematopoietic development, and the clinical manifestations that result.
Abstract: The GATA family of transcription factors, including the founding member, GATA-1, have an important role in gene regulation. GATA-1 is integral to successful hematopoiesis. A wide variety of mutations in GATA-1 affect its function, as well as its interaction with its cofactors (especially Friend of GATA) and the genes upon which GATA-1 acts. Here we review the known mutations, focusing on the specific alterations within the amino acid sequence, the resulting effect on hematopoietic development, and the clinical manifestations that result. Attention is also paid to the relationship between Trisomy 21, also known as Down syndrome, and the phenomenon of a truncated GATA-1, named GATA-1s. The evidence for specific interaction between GATA-1 and chromosome 21, which may explain the correlation between these two mutations, is briefly reviewed.
TL;DR: Bioinformatic analysis revealed that neurodevelopment, differentiation of neuroglia, apoptosis, cell cycle, and signaling pathways including ERK/MAPK, protein kinase C, phosphatidylinositol 3-kinase, m-TOR and calcium signaling are likely targets of these miRNAs.
Abstract: Down syndrome (DS; trisomy 21) is one of the most common genetic causes of intellectual disability, which is attributed to triplication of genes located on chromosome 21. Elevated levels of several microRNAs (miRNAs) located on chromosome 21 have been reported in human DS heart and brain tissues. The Ts65Dn mouse model is the most investigated DS model with a triplicated segment of mouse chromosome 16 harboring genes orthologous to those on human chromosome 21. Using ABI TaqMan miRNA arrays, we found a set of miRNAs that were significantly up- or downregulated in the Ts65Dn hippocampus compared to euploid controls. Furthermore, miR-155 and miR-802 showed significant overexpression in the Ts65Dn hippocampus, thereby confirming results of previous studies. Interestingly, miR-155 and miR-802 were also overexpressed in the Ts65Dn whole blood but not in lung tissue. We also found overexpression of the miR-155 precursors, pri- and pre-miR-155 derived from the miR-155 host gene, known as B cell integration cluster, suggesting enhanced biogenesis of miR-155. Bioinformatic analysis revealed that neurodevelopment, differentiation of neuroglia, apoptosis, cell cycle, and signaling pathways including ERK/MAPK, protein kinase C, phosphatidylinositol 3-kinase, m-TOR and calcium signaling are likely targets of these miRNAs. We selected some of these potential gene targets and found downregulation of mRNA encoding Ship1, Mecp2 and Ezh2 in Ts65Dn hippocampus. Interestingly, the miR-155 target gene Ship1 (inositol phosphatase) was also downregulated in Ts65Dn whole blood but not in lung tissue. Our findings provide insights into miRNA-mediated gene regulation in Ts65Dn mice and their potential contribution to impaired hippocampal synaptic plasticity and neurogenesis, as well as hemopoietic abnormalities observed in DS.
TL;DR: The B chromosome may have evolved from a small chromosomal fragment followed by the invasion of the proto-B chromosome by several repeated DNA families, based on cytogenetic mapping data.
Abstract: B chromosomes are additional chromosomes widely studied in a diversity of eukaryotic groups, including fungi, plants and animals, but their origin, evolution and possible functions are not clearly understood. To further understand the genomic content and the evolutionary history of B chromosomes, classical and molecular cytogenetic analyses were conducted in the cichlid fish Astatotilapia latifasciata, which harbor 1–2 B chromosomes. Through cytogenetic mapping of several probes, including transposable elements, rRNA genes, a repeated DNA genomic fraction (C0t − 1 DNA), whole genome probes (comparative genomic hybridization), and BAC clones from Oreochromis niloticus, we found similarities between the B chromosome and the 1st chromosome pair and chromosomes harboring rRNA genes. Based on the cytogenetic mapping data, we suggest the B chromosome may have evolved from a small chromosomal fragment followed by the invasion of the proto-B chromosome by several repeated DNA families.
TL;DR: A case of a male child referred for genetic investigation of severe language delay is reported, lending support to the hypothesis that the Protocadherin11X/Y gene plays a role in language development in humans and that rare copy number variation is a possible mechanism for communication disorders.
Abstract: Protocadherin11 is located on both the X and Y chromosomes in Homo sapiens but only on the X chromosome in other hominid species. The pairing of PCDH11Y with PCDH11X arose following a duplicative 3.5 Mb translocation from the ancestral X chromosome to the Y chromosome several million years ago. The genes are highly expressed in fetal brain and spinal cord. The evolutionary consequence of this duplication has been proposed to include the sexual dimorphism of cerebral asymmetry and the hominid specific transition to the capacity for language. We report a case of a male child referred for genetic investigation of severe language delay. Microarray analysis indicated the presence of a 220 Kb intragenic deletion at Xq21.31 involving the PCDH11X gene. Fluorescence in situ hybridization using a BAC probe mapping to intron 2 of the Protocadherin11X/Y gene pair confirmed loss of the locus on both the X and Y chromosomes. The X chromosome deletion was maternally inherited, but the Y chromosome deletion was found to be a de novo occurrence in this child. This finding lends support to the hypothesis that the Protocadherin11X/Y gene plays a role in language development in humans and that rare copy number variation is a possible mechanism for communication disorders.
TL;DR: Quantitative assessment of structural and mechanical properties of the femur in Ts65Dn and control mice revealed significant deficiencies in trabecular and cortical bone architecture, bone mineral density, bone formation, and bone strength in trisomic bone, demonstrating that trisomy significantly affects both the craniofacial and appendicular skeleton.
TL;DR: Data indicate that in the context of a DS background, ALK2-mediated reduction of BMP signaling may contribute to CHDs.
Abstract: Down's syndrome (DS), resulting from an additional copy of chromosome 21 (trisomy 21), is frequently associated with congenital heart defects (CHDs). Although the increased dosage of chromosome 21 sequences is likely to be part of the etiology of cardiac defects, only a proportion of DS patients exhibit a congenital heart defect (birth prevalence 40-60%). Through a large-candidate gene-sequencing screen in patients with atrioventricular septal defects, substitutions were identified in bone morphogenetic protein (BMP) type I receptor ALK2 and two other genes in a patient with DS and a primum-type atrial septal defect. Structural modeling of the cytoplasmic domain of the ALK2 receptor suggests that H286 is in close proximity to the nucleotide-binding site of the kinase domain. We investigated whether this p.His286Asp substitution altered ALK2 function by using both in vitro as well as in vivo assays. The p.His286Asp variant demonstrated impaired functional activity as measured by BMP-specific transcriptional response assays. Furthermore, mild dominant-interfering activity was observed in vivo compared with wild-type ALK2 as determined by RNA injection into zebrafish embryos. These data indicate that in the context of a DS background, ALK2-mediated reduction of BMP signaling may contribute to CHDs.
TL;DR: Tc1 and Tc1/Ms4Yah mice show specific exploratory behaviour in the open field and exhibit impaired social preference, and memory impairment in T c1 mice is not affected by the deletion of the Cstb–Prmt2 region.
TL;DR: The results of the analyses of a female patient diagnosed with maternal uniparental disomy of chromosome 14 and West syndrome who carried a small supernumerary marker chromosome provide further evidence that not only duplication but also a small increase in the dosage of FOXG1 could cause infantile spasms.
Abstract: FOXG1 on chromosome 14 has recently been suggested as a dosage-sensitive gene. Duplication of this gene could cause severe epilepsy and developmental delay, including infantile spasms. Here, we report on a female patient diagnosed with maternal uniparental disomy of chromosome 14 and West syndrome who carried a small supernumerary marker chromosome. A chromosomal analysis revealed mosaicism of 47,XX, + mar[8]/46,XX[18]. Spectral karyotyping multicolor fluorescence in situ hybridization analysis confirmed that the marker chromosome was derived from chromosome 14. A DNA methylation test at MEG3 in 14q32.2 and microsatellite analysis using polymorphic markers on chromosome 14 confirmed that the patient had maternal uniparental disomy 14 as well as a mosaic small marker chromosome of paternal origin containing the proximal long arm of chromosome 14. Microarray-based comparative genomic hybridization analysis conclusively defined the region of the gain of genomic copy numbers at 14q11.2-q12, encompassing FOXG1. The results of the analyses of our patient provide further evidence that not only duplication but also a small increase in the dosage of FOXG1 could cause infantile spasms.
TL;DR: Observations indicated that previously unrecognized complex events, involving microhomology-mediated end joining, preceded or accompanied initiation of the BFB cycle, providing insight into potential mechanisms involved in the formation of iAMP21.
Abstract: A distinct sub-group of B-cell precursor acute lymphoblastic leukemia, defined by intrachromosomal amplification of chromosome 21 (iAMP21), is restricted to older children and has been associated with a poor outcome. Accurate diagnosis is important for appropriate risk stratification for treatment. It could be improved by understanding the initiating mechanism. iAMP21 is characterized by amplification of a 5.1-24 Mb region of chromosome 21, which includes the RUNX1 gene. It is thought to arise through a breakage-fusion-bridge (BFB) mechanism. Breakpoints initiating BFB cycles were determined from recent array data from 18 patients. Three occurred within the PDE9A gene. Other patients with breakpoints in PDE9A were identified by fluorescence in situ hybridization and molecular copy number counting. Sequencing defined a 1.7 Kb breakpoint cluster region, positioned 400 bp distal to an extensive region enriched for CA repeats with the potential to form Z-DNA. None of the rearranged sequences showed the inverted repeat structure characteristic of BFB; instead PDE9A was fused to intergenic regions of chromosome 21 or to genes on other chromosomes. These observations indicated that previously unrecognized complex events, involving microhomology-mediated end joining, preceded or accompanied initiation of the BFB cycle. A chi-like heptomer, CCTCAGC, contained four of the breakpoints, two within PDE9A and two within partner Alu-repeat sequences. This heptomer was closely homologous to a breakpoint hotspot within the TCF3 gene, suggesting involvement of a common novel recombinogenic mechanism that might also contribute to the recombinogenic potential of Alu repeats. These findings provide insight into potential mechanisms involved in the formation of iAMP21.
TL;DR: Over 40 years of age persons with Down syndrome develop a form of dementia with several clinical and neuropathologic characteristics of Alzheimer’s disease (AD), although with an earlier age of onset.
Abstract: Down syndrome (DS) is a chromosomal abnormality due to partial or complete triplication of chromosome 21 (HSA21), and is the most common genetic cause of intellectual disability. DS may be considered a multifactorial disease, where an abnormal expression of trisomic genes arises not only from genetic, but also environ mental factors [1]. Thus, trisomy leads to a deregulated scenario that also affects disomic genes and that ultimately results in largely different phenotypes [2]. In fact, DS patients present a high variability of symptoms, including premature aging, mental retardation and Alzheimer’s-like dementia. Thus, above 40 years of age these persons develop a form of dementia with several clinical and neuropathologic characteristics of Alzheimer’s disease (AD), although with an earlier age of onset [3].
TL;DR: Prenatal diagnosis of major congenital malformations should alert one to the possibility of chromosomal abnormalities and multiplex ligation-dependent probe amplification and aCGH have the advantage of rapid aneuploidy diagnosis of common aneuPLoidies in cases with major congenitals malformation.
Abstract: Objective To report five cases of major congenital malformations associated with common aneuploidies detected by rapid aneuploidy diagnosis Case Reports The fetus in the first case presented cebocephaly, semilobar holoprosencephaly, and tetralogy of Fallot on ultrasound at 25 gestational weeks Cordocentesis using multiplex ligation-dependent probe amplification to detect aneuploidies of chromosomes X, Y, 13, 18, and 21 in uncultured cord blood revealed three copies of all targets on chromosome 13 consistent with the diagnosis of trisomy 13 The fetus in the second case presented bilateral choroid plexus cysts, congenital diaphragmatic hernia, and club foot on ultrasound at 18 gestational weeks Amniocentesis using array-based comparative genomic hybridization (aCGH) in uncultured amniocytes revealed a gain in the DNA dosage of chromosome 18 consistent with the diagnosis of trisomy 18 The fetus in the third case presented aortic stenosis and nuchal edema on ultrasound at 22 gestational weeks Amniocentesis using aCGH in uncultured amniocytes revealed a result of monosomy X and Turner syndrome The fetus in the fourth case presented nuchal cystic hygroma and ventriculomegaly on ultrasound at 17 gestational weeks Amniocentesis using aCGH in uncultured amniocytes revealed a gain in the DNA dosage of chromosome 21 consistent with the diagnosis of trisomy 21 The fetus in the fifth case presented holoprosencephaly, omphalocele, and hydronephrosis on ultrasound at 17 gestational weeks Amniocentesis using aCGH in uncultured amniocytes revealed a gain in the DNA dosage of chromosome 13 consistent with the diagnosis of trisomy 13 Conclusions Prenatal diagnosis of major congenital malformations should alert one to the possibility of chromosomal abnormalities Multiplex ligation-dependent probe amplification and aCGH have the advantage of rapid aneuploidy diagnosis of common aneuploidies in cases with major congenital malformations
TL;DR: A link between overexpression of specific ITSN1 isoforms and behavioral phenotypes is revealed and has implications for human neurodegenerative diseases such as Down’s syndrome and Alzheimer's disease.
Abstract: Intersectin 1 (ITSN1) is a human chromosome 21 (HSA21) gene product encoding a multidomain scaffold protein that functions in endocytosis, signal transduction, and is implicated in Down's syndrome, Alzheimer's Disease, and potentially other neurodegenerative diseases through activation of c-Jun N-terminal kinase. We report for the first time that ITSN1 proteins are elevated in individuals with Down's syndrome of varying ages. However, ITSN1 levels decreased in aged cases with Down's syndrome with Alzheimer's disease-like neuropathology. Analysis of a novel ITSN1 transgenic mouse reveals that ITSN1 overexpression results in a sex-dependent decrease in locomotor activity. This study reveals a link between overexpression of specific ITSN1 isoforms and behavioral phenotypes and has implications for human neurodegenerative diseases such as Down's syndrome and Alzheimer's disease.