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Biomedical subjects

J M Delabar

Publications and source records attributed to J M Delabar.

At least 19 recordsLinked to original sources
PubMed2006

C21orf5, a human candidate gene for brain abnormalities and mental retardation in Down syndrome.

Mental retardation represents the more invalidating pathological aspect of trisomy 21 and has a hard impact on public health. The dosage imbalance of chromosome 21 genes could be the cause of neurological alterations and mental retardation seen in Down syndrome. We studied C21orf5 that we have demonstrated to be overexpressed in Down syndrome tissues, as a candidate gene for trisomy 21. A new optical technology (Rachidi et al., 2000) was used to compare signal intensity and cell density in presumptive embryonic brain compartments, at their boundaries and in higher specialized brain centres during fetal lifespan. We showed a developmentally regulated transcriptional activity of C21orf5 and a regional and cellular specific distribution of gene transcripts during human embryonic and fetal development. A wide but differential expression was detected in the nervous system during embryogenesis with a relatively lower level in the forebrain than in the midbrain and hindbrain and the highest transcription intensity in the future cerebellum. This developmentally regulated expression is maintained during post-embryogenesis and evolves selectively in fetal cerebral, hippocampal and cerebellar areas. Differential and cellular specificity were detected in hippocampus with higher C21orf5 mRNA level in the pyramidal cells compared to granular cells of the dentate gyrus. The expression pattern detected in cortical and cerebellar structures correlates well to the altered cortical lamination and to the lower size of the cerebellum observed in Down syndrome patients. In addition, the patterned differential expression detected in the medial temporal-lobe system, including hippocampal formation and perirhinal cortex, working as control centres of the memory circuits and involved in cognitive processes and memory storage, also corresponds to abnormal brain regions seen in Down syndrome patients. The C21orf5 selective expression in the key brain structures for learning and memory suggests that C21orf5 overexpression could participate in mental retardation pathogenesis in Down syndrome patients.

Brain↗
PubMed2003

Chromosome 21 KIR channels in brain development.

Two KIR (K+ Inwardly Rectifying) channel genes have been identified on chromosome 21, in a region associated with important phenotypic features of trisomy 21, including mental retardation: KIR3.2 (GIRK2) and KIR4.2. We analysed the expression of these channel genes in developing human and mouse brains to determine the possible role of the corresponding channels in brain development and function. KIR3.2, which has been extensively studied in the mouse, was found to be expressed in the human cerebellum during development. The KIR4.2 channel is expressed later in development in both mice and humans. We compared the expression of these channels in terms of RNA and protein levels and discussed the potential synergy and consequences of the overexpression of these channels in Down's syndrome brain development.

Animals↗
PubMed2001

The CASK/Lin-2 Drosophila homologue, Camguk, could play a role in epithelial patterning and in neuronal targeting.

Drosophila Camguk (Cmg) is a member of the CAMGUK subfamily of the MAGUK family of proteins which are localized at cell junction and other plasma membrane specialized regions, from worms to mammals. The protein structure of Cmg, as the other CAMGUK proteins, is characterized by only one PDZ domain and an additional CaM kinase domain, similar to CaMKII. While the mammalian ortholog CASKs play an important role in synaptic protein targeting and in synaptic plasticity, the Drosophila Cmg role is unknown. To study its potential role, we reported a detailed analysis of mRNA distribution of the Drosophila cmg gene at cellular and developmental level, during embryonic, larval, pupal and adult stages. The transient cmg transcription in midgut and Malpighian tubules may suggest a potential function in cell junction formation and in epithelial tissue patterning. Interestingly, cmg transcription increases substantially during embryonic neuroblast proliferation, becoming predominant in the developing central nervous system (CNS) during embryonic and postembryonic development stages and in the mature brain. In addition, a high transcriptional level was detected in the eye imaginal discs and in the adult retina, demonstrating a specific and continuous expression of cmg in neuroblasts and photoreceptor neurons, from the onset of cytodifferentiation. Our findings suggest that Cmg could play a potential role in transmembrane protein targeting, particularly in synapses. These observations suggest the existence of a common highly conserved mechanism involved in forming and maintaining proper synaptic protein targeting, which are fundamental features of synaptic plasticity, learning and memory. Through its function, the CaM kinase domain-containing Cmg may be involved in signal transduction cascade. Its potential relation to Calmodulin and CaMKII is discussed.

Animals↗
PubMed2001

Assessing implications between genotypic and phenotypic variables through lattice analysis.

A previous paper assessed a "Molecular Mapping of Twenty-Four Features of Down Syndrome on Chromosome 21" (Delabar et al., 1993), by analyzing the genotypes/phenotypes of patients suffering from partial trisomy. The mapping was defined through implications--each feature was mapped to the conjunction of cytogenetic bands that were shared by all patients having that feature. In the present paper, we extend that approach to determine how far those implications depart from defining equivalences. Finding equivalences is important. Local equivalences permit a genetic characterization of a feature. And if global equivalences held for all features, that set of bands would be sufficient to characterize the various phenotypes observed in individuals with partial trisomy 21. To extend the earlier approach, we examine the structure of equivalences as well as the structure of implications. We examine both conjunctions of bands and conjunctions of features. The use of Galois lattices permits simultaneous evaluation of both kinds of structures. Each Galois lattice is labeled with a basis (minimal generating set) of implications going from conjunctions of features into bands and those going from conjunctions of bands into features. Analysis reveals that about half of the conjunctions of bands that characterize the genetic structure embody equivalences. This allows us to improve the genetic description of features and to specify minimal sets of questions that need to be investigated to make the global genetic description more precise.

Chromosome Banding↗
PubMed2000

C21orf5, a novel human chromosome 21 gene, has a Caenorhabditis elegans ortholog (pad-1) required for embryonic patterning.

To contribute to the development of the transcription map of human chromosome 21 (HC21), we isolated a new transcript, C21orf5 (chromosome 21 open reading frame 5), encoding a predicted 2298-amino-acid protein. Analysis of the genomic DNA sequence revealed that C21orf5 consists of 37 exons that extend over 130 kb and maps between the CBR3 (carbonyl reductase 3) and the KIAA0136 genes. Northern blot analyses showed a ubiquitously expressed RNA species of 8.5 kb. RNA in situ hybridization on brain sections of normal human embryos revealed a strong labeling in restricted areas of the cerebral cortex. In silico analysis of the deduced C21orf5 protein revealed several highly probable transmembrane segments but no known protein domains or homology with known proteins. However, there were significant homologies to several hypothetical Caenorhabditis elegans proteins and Drosophila melanogaster genomic sequences. To investigate the function of C21orf5, we isolated the cDNA of the C. elegans ortholog and performed double-stranded RNA-mediated genetic interference experiments. The major phenotype observed in the progeny of injected animals was embryonic lethality. Most of the tissues of the embryo failed to undergo proper patterning during gastrulation, and morphogenesis did not occur; thus we termed the ortholog pad-1, for patterning defective 1. These results indicated that pad-1 is essential for the development and the survival of C. elegans. This study provides the first example of the use of C. elegans as a model to study the function of genes on human chromosome 21 that might be involved in Down syndrome.

Amino Acid Sequence↗
PubMed2000

Characterization of a novel gene, C21orf6, mapping to a critical region of chromosome 21q22.1 involved in the monosomy 21 phenotype and of its murine ortholog, orf5.

Phenotypic and molecular analyses of patients with partial chromosome 21 monosomy enabled us to define a region, spanning 2.4 Mb between D21S190 and D21S226, associated with arthrogryposis, mental retardation, hypertonia, and several facial anomalies. The markers of the region were used to screen a total human PAC library (Ioannou, RZPD). We isolated 57 PACs, which formed primary contigs. EST clusters (UNIGENE collection) located in a 6-Mb interval, between D21S260 and D21S263, were mapped in individual bacterial clones. We mapped the WI-17843 cluster to the PAC clone J12100, which contains the two anchor markers LB10T and LA329. The open reading frame extends over 960 bp, with three putative start codons. The 1695-bp cDNA containing a polyadenylation signal should correspond to the full-length cDNA. From the genomic sequence, we deduced that the gene contained five exons and that there was a putative promoter sequence upstream from exon 1. In silico screening of DNA databases revealed similarity with a murine EST. The corresponding cDNA (1757 bp) sequence was very similar (>85%) to the human cDNA and had an open reading frame of 876 nucleotides. Somatic hybrid mapping localized the cDNA to mouse chromosome 16. EST analyses and RT-PCR indicated that the third exon in the human gene (exon 2 in the mouse) undergoes alternative splicing. Northern blot hybridization showed that the gene was ubiquitously expressed in humans and mice. The longest mouse clone was used to generate riboprobes, which were hybridized to murine embryos at stages E-9.5, E-10.5, E-12.5, E-13.5, and E-14.5-15, to study the pattern of expression during development. Ubiquitous labeling was observed, with strong signals restricted to limited areas of the telencephalon, the mesencephalon, and the interrhombomeric regions in the central nervous system, and other regions of the body such as the limb buds, branchial arches, and somites.

Amino Acid Sequence↗
PubMed2000

Regional and cellular specificity of the expression of TPRD, the tetratricopeptide Down syndrome gene, during human embryonic development.

The TPRD gene (tetratricopeptide (TPR) containing Down syndrome gene) is one of the candidate genes in the Down syndrome chromosomal region-1. Duplication of this gene may be the cause of major phenotypic features of Down syndrome. Here we show that the TPRD expression is developmentally regulated during human embryogenesis. At the earliest stages of development (Carnegie 8-12) TPRD expression is ubiquitous. At later developmental stages (Carnegie stages 14, 16 and 18), it becomes restricted to the nervous system, as is the case for the mtprd gene during mouse development. We extended our analysis of TPRD expression during fetal development of the human nervous system (13, 22 and 24 weeks). A new oblique illumination technique was used to compare signal intensity and cell density. Some regions of the nervous system such as the external cortical layers of the brain, and the inner neuroblastic layer of the eye, strongly express the TPRD gene.

Cerebral Cortex↗
PubMed1999

Dynamic expression pattern of Ca(2+)/calmodulin-dependent protein kinase II gene in the central nervous system of Drosophila throughout development.

Calcium/calmodulin-dependent protein kinase II (CaM KII) is thought to be involved in the majority of the neuronal functions mediated by intracellular free Ca(2+), and has been implicated in long-term potentiation, learning, and memory. In this work, we have examined in detail the RNA expression pattern for the Drosophila CaM KII gene by in situ hybridization, during embryonic, larval, pupal, and adult stages. Our results indicate that expression of CaM KII was homogeneous in early embryos, but that during development the gene transcription rapidly became restricted to neuroblasts and their progeny in the nervous system. This predominant expression in the nervous system is maintained during late embryogenesis and post-embryonic development. A signal compartmentalization appeared in the larval central nervous system, where the CaM KII expression became progressively concentrated in the anterior ganglia. In the adult brain, a specific expression was more abundant in a subset of neurons around the central brain, particularly the mushroom bodies and the central complex, structures that play an important role in learning and memory.

Animals↗
PubMed1999

Developmentally regulated expression of mtprd, the murine ortholog of tprd, a gene from the Down syndrome chromosomal region 1.

The gene tprd, which contains three tetratricopeptide domains, has been recently localized in the Down syndrome (DS) chromosomal region 1. We have cloned a cDNA encoding part of the murine ortholog of tprd and used it to characterize the expression pattern of this gene during development and at the adult stage. At E8.5 the expression is uniform. In the later stages of embryogenesis, although expression remains ubiquitous, a pattern of tissues with particularly high expression develops: the strong expression is restricted to non proliferating zones of the nervous system such as the external layer of the cortex, the spinal cord, the cranial and root ganglia and the nerves. In the brain of adult mouse the strongest signals are observed in layers II-III and V-VI of the cortex, in the hippocampus and in the cerebellum, which correspond to the abnormal brain regions seen in DS patients.

Animals↗
PubMed1998

Expression of the mnb (dyrk) protein in adult and embryonic mouse tissues.

Mnb is a human homologue of the Drosophila minibrain gene which encodes a serine/threonine protein kinase that is required in distinct neuroblast proliferation centers during postembryonic neurogenesis. The high degree of homology of the human gene to the murine gene (dyrk) allowed us to use a human polyclonal anti-mnb antibody to study the expression pattern of the protein in adult and embryonic mouse tissues. Western blot analysis and immunohistochemical methods were used to define the detailed distribution of mnb in adult brain and 17 days mouse embryos. The results show a high expression in the cerebral cortex, the cerebellum, the hippocampus which is in accordance with previous reports of in situ hybridization studies using mRNA probes but also a very strong expression in the epithelial layers of the skin, the retina, the tongue, the intestine and the kidney which has not been described before. Since epithelial cells are highly mitotic cells and since mnb shares sequence similarities with the cdk kinases involved in the regulation of cell division, this result may indicate a important role of mnb in the cell cycle control.

Aging↗
PubMed1998

Transcriptional map of the 2.5-Mb CBR-ERG region of chromosome 21 involved in Down syndrome.

The region of chromosome 21 between genes CBR and ERG (CBR-ERG region), which spans 2.5 Mb on 21q22.2, has been defined by analysis of patients with partial trisomy 21. It contributes significantly to the pathogenesis of many characteristics of Down syndrome, including morphological features, hypotonia, and mental retardation. Cosmid contigs covering 80% of the region were constructed and EcoRI maps produced. These cosmids were used for exon trapping and cDNA selection from three cDNA libraries (fetal brain, fetal liver, and adult skeletal muscle). Isolated exons and cDNAs were mapped on the EcoRI map, organized into contigs, sequenced, and used as probes for Northern blot analysis of RNA from fetal and adult tissues. We identified 27 genuine or highly probable transcriptional units evenly distributed along the CBR-ERG region. Eight of the transcriptional units are known genes.

Chromosome Mapping↗
PubMed1998

High resolution physical mapping and identification of transcribed sequences in the Down syndrome region-2.

The identification and mapping of genes within the Down syndrome region is an important step toward a complete understanding of the pathogenesis of this disorder. The objective of the present work is to identify and map genes within the Down syndrome region-2. Chromosome 21 cosmid clones corresponding to "cosmid pockets" 121-124 have been first used as a starting material for generation of a single high resolution integrated cosmid/PAC contig with full EcoRI/SmaI restriction map. The integrated contig has been further anchored to genetic and physical maps through the positioning of 6 markers in the following order: ACTL5-D21S3-684G2T7-D21S71-D21S343-D21S 268. The entire contig covers 342 kb of the Down syndrome region-2 of chromosome 21. Subsequently, we have isolated, identified, and mapped four novel cDNAs which we have named N143, N144, CHD/333, and 90/3H1 and a potentially transcribed genomic sequence (E05133T7). Additionally, we have accurately located a previously described gene, the WRB gene, between the markers ACTL5-D21S268 within this Down Syndrome Region-2.

Chromosome Mapping↗
PubMed1998

Conservation of pericentromeric duplications of a 200-kb part of the human 21q22.1 region in primates.

We analyzed the conservation of large paralogous regions (more than 200 kb) on human chromosome regions 21q22.1 and 21q11.2 and on pericentromeric regions of chromosomes 2, 13, and 18 in three nonhuman primate species. Orthologous regions were found by FISH analysis of metaphase chromosomes from Gorilla gorilla, Pan troglodytes, and Pongo pygmaeus. Only one orthologous region was detected in chromosomes of P. pygmaeus, showing that the original locus was at 21q22.1 and that the duplication arose after the separation of Asian orangutans from the other hominoids. Surprisingly, the paralogous regions were more highly conserved in gorilla than in chimpanzee. PCR amplification of STSs derived from sequences of the chromosome 21 loci and low-stringency FISH analysis showed that this duplication occurred recently in the evolution of the genome. Different rates of sequence evolution through substitutions or deletions, after the duplication, may have resulted in diversity between closely related primates.

Animals↗
PubMed1997

High-resolution physical mapping of a 6.7-Mb YAC contig spanning a region critical for the monosomy 21 phenotype in 21q21.3-q22.1.

Deletion of genes from the chromosome 21 region between APP and SOD1 is a potential cause of some of the major phenotypic features of monosomy 21 patients. Fine physical mapping helps identify potential candidate genes. After selecting nonchimeric YACs by FISH analysis, we determined their marker contents by PCR and hybridization studies. Fifteen YACs were chosen and mapped by restriction enzyme analysis and labeling of end fragments. We localized 55 markers, including 31 STSs, 10 YAC ends, and 4 NotI linking clones, along a 6.7-Mb contig. This map facilitates transcriptional analysis of this region and construction of ready-to-sequence contigs. Furthermore, FISH mapping of two patients with partial monosomy 21 using YAC and cosmid clones allowed us to define more accurately the telomeric border of the critical region between markers S226 and S213.

Abnormalities, Multiple↗
PubMed1997

A case of apparent trisomy 21 without the Down's syndrome phenotype.

We describe a case of apparent trisomy 21 that does not fulfill the criteria for the clinical diagnosis of Down's syndrome (DS). Our patient was subjected to karyotype analysis and found to have full, non-mosaic trisomy 21 in both blood lymphocytes and skin fibroblasts, while examination of the term placenta, which was performed earlier in the course of a different study, had shown mosaicism (73%) for trisomy 21. FISH analysis showed no obvious rearrangement of the DS chromosomal region in any of the chromosomes 21. Molecular analysis using polymorphic markers on chromosome 21 verified the existence of trisomy for the entire long arm of the chromosome and showed that the origin of the extra chromosome was maternal and was probably the result of a mitotic error. In contrast with the above, the clinical evaluation using the Jackson checklist of 25 signs failed to establish the diagnosis of DS. We believe that our patient might present mosaicism in other tissues that are not available for analysis and can be regarded as an extreme example in the continuous spectrum of karyotype phenotype associations in mosaic cases.

Down Syndrome↗
PubMed1995

Down syndrome-critical region contains a gene homologous to Drosophila sim expressed during rat and human central nervous system development.

Many features of Down syndrome might result from the overdosage of only a few genes located in a critical region of chromosome 21. To search for these genes, cosmids mapping in this region were isolated and used for trapping exons. One of the trapped exons obtained has a sequence very similar to part of the Drosophila single-minded (sim) gene, a master regulator of the early development of the fly central nervous system midline. Mapping data indicated that this exonic sequence is only present in the Down syndrome-critical region in the human genome. Hybridization of this exonic sequence with human fetal kidney poly(A)+ RNA revealed two transcripts of 6 and 4.3 kb. In situ hybridization of a probe derived from this exon with human and rat fetuses showed that the corresponding gene is expressed during early fetal life in the central nervous system and in other tissues, including the facial, skull, palate, and vertebra primordia. The expression pattern of this gene suggests that it might be involved in the pathogenesis of some of the morphological features and brain anomalies observed in Down syndrome.

Amino Acid Sequence↗
PubMed1994

Cloning and characterization of a 135- to 500-kb region of homology on the long arm of human chromosome 21.

The polymorphic marker D21S190 was initially isolated from a chromosome 21 phage library and mapped to two loci: one in 21q11.1 (proximal locus) and the other one in 21q22.1 (distal locus). To characterize the region of homology revealed with D21S190, we have screened two different chromosome 21 YAC libraries and one chromosome 21 cosmid library. Fluorescence in situ hybridization on normal human chromosomes of YACs, cosmids, and phages positive with D21S190 confirmed the existence of two homologous regions on the long arm of chromosome 21. Among the positive YACs, four (HY67, 2D7y21, 2D11y21, and 1B1y21) were selected and oriented relative to each other, forming a 2-Mb contig in the distal locus, including D21S54. Hybridization of YAC extremities to a panel of somatic cell hybrids containing various portions of chromosome 21 showed that the proximal locus is located between the breakpoints of 2Fu(r)1 and ACEM and the distal locus between the breakpoints of ACEM and 6918. The proximal and the distal breakpoints of JC6 are both included in the region of homology. We have constructed a restriction map of HY67, 2D7y21, and 2D11y21 spanning 1 Mb and including several markers: D21S294, D21S296, and the new STSs corresponding to YAC extremities. The region of homology encompasses 135-500 kb and has the same orientation in the distal and in the proximal locus, which are at least 12 Mb apart. It is lacking a NotI site but does contain clusters of GC-rich restriction sites, which are candidate regions for as yet unidentified genes.

Blotting, Southern↗