1,721,029 research outputs found
Trisomy 21: research for a cure and rediscovery of the thought of Jerome Lejeune
No full textDown syndrome (DS) is the most frequent constitutional form of intellectual disability in humans. In 1958 Jerome Lejeune discovered that children with DS have one extra copy of chromosome 21 (trisomy 21) in their cells. Lejeune considered the trisomic cells as ‘‘drug addicted’’, intoxicated by the excess of gene products that are formed due to the presence of the additional chromosome. If we knew the pathogenetic mechanisms we could devise a more specific therapy. Lejeune, a genial geneticist and biochemist, was also a pediatrician who visited thousands of children with intellectual disability, encouraging their families, highlighting the enrichment in humanity experienced by so many families because of the presence of a person with DS and not only the problems. He dedicated all of his life and so much love to these children, and at the same time he would correct the biochemical errors which hamper the full expression of their human abilities and he used to say: ‘‘Hate the disease, love the patient: that is the practice of medicine’’. To date, no therapy is recognized as being effective in improving the cognitive abilities of persons with DS. Research was slowed by the fact that so many studies have been focused on prenatal diagnosis of the syndrome rather than on its treatment. Following the encounter with Lejeune’s history and work, we have started a systematic study of DS to integrate clinical, biochemical, genetic and bioinformatic data in order to identify novel therapeutic targets for this form of trisomy
Identification of minimal eukaryotic introns through GeneBase, a user-friendly tool for parsing the NCBI Gene databank
Full text linkWe have developed GeneBase, a full parser of the National Center for Biotechnology Information (NCBI) Gene database, which generates a fully structured local database with an intuitive user-friendly graphic interface for personal computers. Features of all the annotated eukaryotic genes are accessible through three main software tables, including for each entry details such as the gene summary, the gene exon/intron structure and the specific Gene Ontology attributions. The structuring of the data, the creation of additional calculation fields and the integration with nucleotide sequences allow users to make many types of comparisons and calculations that are useful for data retrieval and analysis. We provide an original example analysis of the existing introns across all the available species, through which the classic biological problem of the 'minimal intron' may find a solution using available data. Based on all currently available data, we can define the shortest known eukaryotic GT-AG intron length, setting the physical limit at the 30 base pair intron belonging to the human MST1L gene. This 'model intron' will shed light on the minimal requirement elements of recognition used for conventional splicing functioning. Remarkably, this size is indeed consistent with the sum of the splicing consensus sequence lengths
The human TruB family of pseudouridine synthase genes, including the Dyskeratosis Congenita 1 gene and the novel member TRUB1
Full text linkA novel human gene denominated TruB pseudouridine (psi) synthase homolog 1 (E. coli) (approved symbol, TRUB1) has been identified and characterized. Spanning approximately 40 kb on chromosome 10 and including 8 exons, TRUB1 is the first described human ortholog of bacterial TruB/psi55, a gene involved in tRNA pseudouridinilation. TRUB1 gene encodes a 349-amino acid product, with a VFAVHKPKGPTSA box in positions 71-83 corresponding to motif I of the TruB family (probably involved in conserving protein structure). The TruB domain of TRUB1 lies between W104 and I255, and contains another short motif, GGTLDS AARGVLVV, including the highly conserved D residue that characterizes motif II (involved in uridine recognition and in catalytic function of psi synthases). Northern blot analysis revealed that TRUB1 mRNA is widely expressed in various human tissues (especially heart, skeletal muscle and liver). Phylogenetic analysis of the TruB domain revealed another human gene (approved symbol TRUB2) encoding a conserved TruB domain, located on human chromosome 9. Thus, the human TruB family includes at least three members: i.e. DKC1 (previously identified), TRUB1 and TRUB2. The TRUB1 and TRUB2 products could be the hitherto unidentified human tRNA psi synthases. Although TRUB1 is not highly similar to DKC1/dyskerin (whose mutations cause X-linked dyskeratosis congenita) and putatively affects tRNA rather than rRNA modification, it is the most similar human protein to dyskerin. Study of TRUB1 (and TRUB2) should facilitate understanding of the molecular mechanisms of RNA modification and the involvement of psi synthases in human pathology, including dyskeratosis-like diseases
Integrated differential transcriptome maps of Acute Megakaryoblastic Leukemia (AMKL) in children with or without Down Syndrome (DS)
Full text linkBackground: The incidence of Acute Megakaryoblastic Leukemia (AMKL) is 500-fold higher in children with Down
Syndrome (DS) compared with non-DS children, but the relevance of trisomy 21 as a specific background of AMKL
in DS is still an open issue. Several Authors have determined gene expression profiles by microarray analysis in DS
and/or non-DS AMKL. Due to the rarity of AMKL, these studies were typically limited to a small group of samples.
Methods: We generated integrated quantitative transcriptome maps by systematic meta-analysis from any available
gene expression profile dataset related to AMKL in pediatric age. This task has been accomplished using a tool recently
described by us for the generation and the analysis of quantitative transcriptome maps, TRAM (Transcriptome Mapper),
which allows effective integration of data obtained from different experimenters, experimental platforms and data
sources. This allowed us to explore gene expression changes involved in transition from normal megakaryocytes
(MK, n=19) to DS (n=43) or non-DS (n=45) AMKL blasts, including the analysis of Transient Myeloproliferative Disorder
(TMD, n=20), a pre-leukemia condition.
Results: We propose a biological model of the transcriptome depicting progressive changes from MK to TMD and
then to DS AMKL. The data indicate the repression of genes involved in MK differentiation, in particular the cluster on
chromosome 4 including PF4 (platelet factor 4) and PPBP (pro-platelet basic protein); the gene for the mitogen-activated
protein kinase MAP3K10 and the thrombopoietin receptor gene MPL. Moreover, comparing both DS and non-DS AMKL
with MK, we identified three potential clinical markers of progression to AMKL: TMEM241 (transmembrane protein 241)
was the most over-expressed single gene, while APOC2 (apolipoprotein C-II) and ZNF587B (zinc finger protein 587B)
appear to be the most discriminant markers of progression, specifically to DS AMKL. Finally, the chromosome 21 (chr21)
genes resulted to be the most over-expressed in DS and non-DS AMKL, as well as in TMD, pointing out a key role of
chr21 genes in differentiating AMKL from MK.
Conclusions: Our study presents an integrated original model of the DS AMLK transcriptome, providing the
identification of genes relevant for its pathophysiology which can potentially be new clinical markers
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Cysteine and tyrosine-rich 1 (CYYR1), a novel unpredicted gene on human chromosome 21 (21q21.2), encodes a cysteine and tyrosine-rich protein and defines a new family of highly conserved vertebrate-specific genes
No full textA novel human gene has been identified by in-depth bioinformatics analysis of chromosome 21 segment 40/105 (21q21.1), with no coding region predicted in any previous analysis. Brain-derived DNA complementary to RNA (cDNA) sequencing predicts a 154-amino acid product with no similarity to any known protein. The gene has been named cysteine and tyrosine-rich protein 1 gene (symbol cysteine and tyrosine-rich 1, CYYR1). The CYYR1 messenger RNA was found by Northern blot analysis in a broad range of tissues (two transcripts of 3.4 and 2.2 kb). The gene consists of four exons and spans about 107 kb, including a very large intron of 85.8 kb. Analysis of expressed sequence tags shows high CYYR1 expression in cells belonging to the amine precursor uptake and decarboxylation system. We also cloned the cDNA of the murine ortholog Cyyr1, which was mapped by a radiation hybrid panel on chromosome 16 within the region corresponding to that containing the respective human homolog on chromosome 21. Sequence and phylogenetic analysis led to identification of several genes encoding CYYR1 homologous proteins. The most prominent feature identified in the protein family is a central, unique cysteine and tyrosine-rich domain, which is strongly conserved from lower vertebrates (fishes) to humans but is absent in bacteria and invertebrates
Segmental paralogy in the human genome: A large-scale triplication on 1p, 6p, and 21q
No full textFew cases of large-scale segmental paralogy have been reported in the human genome. We have identified a large (∼500 kb) segment on human chromosome (HC) 21 (21q22) that is triplicated on HC 1 (1p35) and HC 6 (6p12-21). We also identified a new member of CLIC (Chloride intracellular Channel) family on 21q, namely CLIC6. All three segments appear to include three functional members of three different gene families: DSCR1-like (Down Syndrome Candidate Region 1-like), CLIC, and AML/Runt (Acute Myeloid Leukemia/Runt). Molecular evolution analysis shows a common evolutionary origin for the triplicated regions. This finding of a further large-scale genomic triplication that went undetected at previously systematic automated searches provides a new model for gene divergence study and underlines the need for new tools to effectively detect inter-chromosomal similarity. An algorithm to overcome current limitations is proposed
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