Showing papers by "Stylianos E. Antonarakis published in 2003"
University of Pennsylvania1, New York University2, National Institutes of Health3, National Institute for Health and Welfare4, Cardiff University5, University of Bonn6, Johns Hopkins University School of Medicine7, Harvard University8, University of Medicine and Dentistry of New Jersey9, Rutgers University10, Columbia University11, University of Louisville12, University College London13, Uppsala University14, University of Utah15, University of California, Irvine16, Queen's University Belfast17, Virginia Commonwealth University18, University of Helsinki19, University of California, Los Angeles20, University of Geneva21, University of Queensland22, Icahn School of Medicine at Mount Sinai23, University of Iowa24, Washington University in St. Louis25, University of Toronto26
TL;DR: The GSMA produced significant genomewide evidence for linkage on chromosome 2q and suggests that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
Abstract: Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
1,176 citations
Trinity College, Dublin1, National Institutes of Health2, University of Pennsylvania3, University College London4, Indiana University – Purdue University Indianapolis5, University of Birmingham6, Johns Hopkins University School of Medicine7, Icahn School of Medicine at Mount Sinai8, University of Chicago9, University of Helsinki10, University of Antwerp11, University of California, San Diego12, Garvan Institute of Medical Research13, University of New South Wales14, Laval University15, University of Utah16, University of Edinburgh17, Washington University in St. Louis18, University of California, Los Angeles19, University of Bonn20, Dalhousie University21, University of Ottawa22, McGill University23, Université libre de Bruxelles24, Umeå University25, University of California, Irvine26, Macquarie University27, University of Texas Health Science Center at San Antonio28, University of California, San Francisco29, University of Costa Rica30, Aarhus University Hospital31, Odense University Hospital32, University of Geneva33, Hacettepe University34
TL;DR: The present results for the very narrow model are promising but suggest that more and larger data sets are needed to support linkage, as well as suggest that linkage might be detected in certain populations or subsets of pedigrees.
Abstract: Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder-BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A "broad" model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region.
585 citations
TL;DR: It is found that CNGs are significantly more conserved than protein-coding genes and noncoding RNAS (ncRNAs) within the mammalian class from primates to monotremes to marsupials.
Abstract: Analysis of the human and mouse genomes identified an abundance of conserved non-genic sequences (CNGs). The significance and evolutionary depth of their conservation remain unanswered. We have quantified levels and patterns of conservation of 191 CNGs of human chromosome 21 in 14 mammalian species. We found that CNGs are significantly more conserved than protein-coding genes and noncoding RNAS (ncRNAs) within the mammalian class from primates to monotremes to marsupials. The pattern of substitutions in CNGs differed from that seen in protein-coding and ncRNA genes and resembled that of protein-binding regions. About 0.3% to 1% of the human genome corresponds to a previously unknown class of extremely constrained CNGs shared among mammals.
208 citations
TL;DR: A two-stage procedure is developed that exploits the mouse and human genome sequences to produce a set of genes with a much higher rate of experimental verification than previously reported prediction methods, and it is estimated that transcription and splicing can be verified for >1,000 gene predictions identified by this method that do not overlap known genes.
Abstract: A primary motivation for sequencing the mouse genome was to accelerate the discovery of mammalian genes by using sequence conservation between mouse and human to identify coding exons. Achieving this goal proved challenging because of the large proportion of the mouse and human genomes that is apparently conserved but apparently does not code for protein. We developed a two-stage procedure that exploits the mouse and human genome sequences to produce a set of genes with a much higher rate of experimental verification than previously reported prediction methods. RT-PCR amplification and direct sequencing applied to an initial sample of mouse predictions that do not overlap previously known genes verified the regions flanking one intron in 139 predictions, with verification rates reaching 76%. On average, the confirmed predictions show more restricted expression patterns than the mouse orthologs of known human genes, and two-thirds lack homologs in fish genomes, demonstrating the sensitivity of this dual-genome approach to hard-to-find genes. We verified 112 previously unknown homologs of known proteins, including two homeobox proteins relevant to developmental biology, an aquaporin, and a homolog of dystrophin. We estimate that transcription and splicing can be verified for >1,000 gene predictions identified by this method that do not overlap known genes. This is likely to constitute a significant fraction of the previously unknown, multiexon mammalian genes.
121 citations
TL;DR: Mutation analysis of the DACTYLIN gene, suspected to be responsible for SHFM3 in chromosome 10q24, was conducted in seven SHFM patients, and no point mutations were found but a complex rearrangement associated with a approximately 0.5 Mb tandem duplication was demonstrated in all the patients.
Abstract: Split hand-split foot malformation (SHFM) is characterized by hypoplasia/aplasia of the central digits with fusion of the remaining digits. SHFM is usually an autosomal dominant condition and at least five loci have been identified in humans. Mutation analysis of the DACTYLIN gene, suspected to be responsible for SHFM3 in chromosome 10q24, was conducted in seven SHFM patients. We screened the coding region of DACTYLIN by single-strand conformation polymorphism and sequencing, and found no point mutations. However, Southern, pulsed field gel electrophoresis and dosage analyses demonstrated a complex rearrangement associated with a approximately 0.5 Mb tandem duplication in all the patients. The distal and proximal breakpoints were within an 80 and 130 kb region, respectively. This duplicated region contained a disrupted extra copy of the DACTYLIN gene and the entire LBX1 and beta-TRCP genes, known to be involved in limb development. The possible role of these genes in the SHFM3 phenotype is discussed.
105 citations
TL;DR: It is shown that TPTE and TPIP proteins are expressed in secondary spermatocytes and/or prespermatids and the existence of several novel alternatively spliced isoforms of these two proteins with variable number of transmembrane domains is reported.
91 citations
TL;DR: A committee was formed to suggest standards for the description of sequence variants in DNA, RNA, and protein sequences, and it was proposed that the nomenclature should be unequivocal, precise, and short.
Abstract: As part of the Human Genome Variation Society (formerly known as the HUGO Mutation Database Initiative), a committee was formed to suggest standards for the description of sequence variants in DNA, RNA, and protein sequences. The committee proposed that the nomenclature should be unequivocal, precise, and short, and should prevent any possible confusion and follow existing practice as much as possible. To “spread the word,” the nomenclature rules were published at regular intervals. This unit summarizes these nomenclature recommendations, which stimulated a uniform and unequivocal description of sequence variants in literature.
48 citations
TL;DR: It is concluded that sequence variation in the BACE1 or BACE 2 gene is not a significant risk factor for AD; however, a combination of a specific Bace1 allele and APOE ε4 may increase the risk for Alzheimer disease over and above that attributed to APOEε4 alone.
Abstract: Alzheimer disease (AD) is characterized neuropathologically by neurofibrillary tangles and senile plaques. A key component of plaques is A beta, a polypeptide derived from A beta-precursor protein (APP) through proteolytic cleavage catalyzed by beta and gamma-secretase. We hypothesized that sequence variation in genes BACE1 (on chromosome 11q23.3) and BACE2 (on chromosome 21q22.3), which encode two closely related proteases that seem to act as the APP beta-secretase, may represent a genetic risk factor for AD. We analyzed the frequencies of single nucleotide polymorphisms (SNPs) in BACE1 and BACE2 genes in a community-based sample of 96 individuals with late-onset AD and 170 controls selected randomly among residents of the same community. The genotype data in both study groups did not demonstrate any association between AD and BACE1 or BACE2. After stratification for APOE status, however, an association between a BACE1 polymorphism located within codon V262 and AD in APOE epsilon 4 carriers was observed (P = 0.03). We conclude that sequence variation in the BACE1 or BACE 2 gene is not a significant risk factor for AD; however, a combination of a specific BACE1 allele and APOE epsilon 4 may increase the risk for Alzheimer disease over and above that attributed to APOE epsilon 4 alone.
46 citations
TL;DR: 2 new families with MHA/FTNS phenotypes that have been characterized in terms of their mutations, protein localization in megakaryocytes, protein expression, and mRNA stability are described and it is hypothesized that haploinsufficiency of the MYH9 results in a failure to properly reorganize the cytoskeleton in megAKaryocytes as required for efficient platelet production.
45 citations
TL;DR: The molecular cloning and initial characterisation of two splice forms of a novel member of this family, CLIC6, mapping to human chromosome 21 are reported, which contains a GC rich segment and encodes a 10 amino acid motif repeated 14 times in the amino-terminus.
37 citations
TL;DR: Loss of CSTB function due to mutations is consistent with the observed neurodegenerative pathology and phenotype, but the functional link to the epileptic phenotype of EPM1 remains largely unknown.
Abstract: Progressive myoclonus epilepsy 1 (EPM1) or Unverricht-Lundborg disease is a human autosomal recessive neurodegenerative disorder caused by mutations in cystatin B (CSTB). The CSTB gene maps to human chromosome 21 and encodes an inhibitor of lysosomal cysteine proteases. Five point mutations have been found, two of which are seen in numerous unrelated patients. However, the main CSTB mutation in EPM1, even among patients of different ethnic origins, is an expansion of a dodecamer repeat (CCCCGCCCCGCG) in the 5' flanking area of CSTB. Most normal alleles contain either two or three repeats, while rarer normal alleles that are highly unstable contain between 12 and 17 repeats. Mutant expanded alleles have been reported to contain between 30 and 80 copies and are also highly unstable, particularly via parental transmission. There is no apparent correlation between mutant repeat length and disease phenotype. While the repeat expansion is outside the CSTB transcriptional unit, it results in a marked decrease in CSTB expression, at least in certain cell types in vitro. CSTB homozygous knockout mice show some parallels to the phenotype of human EPM1 including myoclonic seizures, development of ataxia and neuropathological changes associated with cell loss via apoptosis. Loss of CSTB function due to mutations is consistent with the observed neurodegenerative pathology and phenotype, but the functional link to the epileptic phenotype of EPM1 remains largely unknown.
TL;DR: Surprisingly, it was found that the PH domain was dispensable for guanine nucleotide exchange activity on Cdc42 in vitro, yet thePH domain enhanced the ability of the DH domain to activate CDC42 signaling in vivo.
TL;DR: A method based on PCR after DNA deamination of the GC‐rich repeat region, which improves the PCR condition to such an extent that it is able to reliably amplify expanded alleles of affected individuals (homozygotes and compound heterozygotes), but also the two allele of full mutation carriers, whose analysis is particularly difficult because of PCR bias and heteroduplex formation between theTwo alleles.
Abstract: The Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1) is an autosomal recessive disorder that is caused by the dysfunction of the cystatin B (CSTB) gene product. In the vast majority of affected cases, mRNA transcription is impaired by a biallelic expansion of a dodecamer repeat within the 5'-untranslated region of the respective gene. Since this minisatellite contains exclusively G and C nucleotides, direct PCR analysis of allele expansion is extremely difficult and error prone. To circumvent these problems, we have developed a PCR assay that is based on the deamination of the DNA prior to amplification. We have developed a method based on PCR after DNA deamination of the GC-rich repeat region, which improves the PCR condition to such an extent that we were not only able to reliably amplify expanded alleles of affected individuals (homozygotes and compound heterozygotes), but also the two alleles of full mutation carriers, whose analysis is particularly difficult because of PCR bias and heteroduplex formation between the two alleles. We used promoter- and repeat-specific primer combinations to investigate whether dodecamer repeat expansion concurs with de novo methylation of the CSTB gene promoter in a similar fashion to other repeat expansion syndromes. We confirmed previous evidence obtained by HpaII digestion and Southern blot analysis that both the promoter and the repeat regions are unmethylated, in both healthy and affected individuals. Thus, in contrast to certain trinucleotide repeat expansion-associated diseases, such as fragile X syndrome (FRAXA) and myotonic dystrophy, methylation analyses can not be utilized for indirect diagnostic testing.
TL;DR: Among the 1138 exons trapped, 1052 of them have been mapped to HC18, and the remaining 86 have not been localized, suggesting that the 850 novel exons may represent hundreds of novel genes on chromosome 18.
Abstract: In a search for novel genes on chromosome 18 (HC18), on which several regions have been linked to bipolar disorder, we applied exon trapping to HC18-specific cosmids. Among the 1138 exons trapped, 1052 of them have been mapped to HC18, and the remaining 86 have not been localized. No exons were localized to genomic regions other than HC18. BLAST database search revealed that 190 exons were identical to 98 Unigenes on HC18; 98 identical to additional 82 clusters of ESTs not present in the HC18 Unigene set; 39 homologous to genes from human and other species (e<10(-3)); and the remaining 811 exons had no significant homology to transcripts in public databases. The mapped exons were compared to the 867 annotated genes on HC18 in the Celera databases; 216 exons were identical to 104 Celera 'genes' and the remaining 836 exons were not found in the Celera databases. On average, there were two exons for a matched transcript (known genes and ESTs). Therefore, the 850 novel exons may represent hundreds of novel genes on chromosome 18.