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PubMed2000

Mutation screening in Rett syndrome patients.

Rett syndrome (RTT) was first described in 1966. Its biological and genetic foundations were not clear until recently when Amir et al reported that mutations in the MECP2 gene were detected in around 50% of RTT patients. In this study, we have screened the MECP2 gene for mutations in our RTT material, including nine familial cases (19 Rett girls) and 59 sporadic cases. A total of 27 sporadic RTT patients were found to have mutations in the MECP2 gene, but no mutations were identified in our RTT families. In order to address the possibility of further X chromosomal or autosomal genetic factors in RTT, we evaluated six candidate genes for RTT selected on clinical, pathological, and genetic grounds: UBE1 (human ubiquitin activating enzyme E1, located in chromosome Xp11.23), UBE2I (ubiquitin conjugating enzyme E2I, homologous to yeast UBC9, chromosome 16p13.3), GdX (ubiquitin-like protein, chromosome Xq28), SOX3 (SRY related HMG box gene 3, chromosome Xq26-q27), GABRA3 (gamma-aminobutyric acid type A receptor alpha3 subunit, chromosome Xq28), and CDR2 (cerebellar degeneration related autoantigen 2, chromosome 16p12-p13.1). No mutations were detected in the coding regions of these six genes in 10 affected subjects and, therefore, alterations in the amino acid sequences of the encoded proteins can be excluded as having a causative role in RTT. Furthermore, gene expression of MECP2, GdX, GABRA3, and L1CAM (L1 cell adhesion molecule) was also investigated by in situ hybridisation. No gross differences were observed in neurones of several brain regions between normal controls and Rett patients.

Adolescent↗
PubMed2002

Nucleotide alteration of retinoblastoma protein-interacting zinc finger gene, RIZ, in human leukemia.

The retinoblastoma protein-interacting zinc finger gene (RIZ) is a zinc-finger type DNA binding protein and is postulated as a member of the nuclear protein-methyltransferase superfamily. RIZ gene encodes for two proteins, RIZ1 and RIZ2. While RIZ1 contains the N-terminal PR (PRDI-BF1 and RIZ homologous)-domain, RIZ2 lacks it. RIZ1 is now considered as a tumor suppressor. We analyzed nucleotide alteration of RIZ gene in human leukemia. The results revealed a single nucleotide polymorphism (SNP), T1704 to A, near the conserved Rb-binding domain, leading to an amino acid change, Asp283 to Glu. Interestingly, 17 of 21 leukemia cell lines are homozygous for the T1704 allele whereas only 2 of 20 normal subjects are homozygous for the allele. In addition, one base pair deletion in the poly (A)9 tract in the coding region near the C-terminal zinc-fingers was identified, resulting in frameshift, in 1 out of 17 leukemia cell lines, but no mutation in samples from 15 patients with acute lymphoblastic leukemia (ALL) and 6 patients with adult T cell leukemia (ATL). In the PR or SH3 (src homology 3) domain of the RIZ gene, no mutation was found. These findings suggest that RIZ may be a possible target of structural alteration leading to leukemia.

Alleles↗
PubMed1984

Analysis of the interaction between DNA and major core protein in adenovirus chromatin by circular dichroism and ultraviolet light induced cross-linking.

Adenovirus chromatin is constituted with three kinds of core proteins, VII, V, and mu, that are coded by the virus genome. Since a hexamer of VII contributes to formation of the nucleosome-like structure of the virion chromatin, we analyzed the interaction between DNA and VII in vitro, by the use of ultraviolet light-induced cross-linking and circular dichroism (CD) spectroscopy. It was observed that DNA and VII in a plain mixture form a structure resembling viral chromatin. The DNA in the virion core or in the simply mixed complex appears to take a tight conformation by superfolding, based on the result that the ellipticity at 275 nm of DNA was reduced to approximately 3,000 degrees, and the wave-length of the positive peak was shifted from 275 to 285 nm. The change in CD spectrum caused by interaction of VII with DNA is similar to that of a protamine rather than that of a histone mixture. The interaction of VII with DNA is preferential, and VII is capable of associating more efficiently with double stranded DNA than with single stranded. The interaction is loosened by salt (0.3 M NaCl) and tightened by magnesium ion. However, the interaction of a precursor core protein pro-VII with DNA was not as tight as that of VII and was not influenced by magnesium ion, presumably because of the existence of a hydrophobic processing sequence in the molecule.

Adenoviruses, Human↗
PubMed2002

Influence of mutation type and location on phenotype in 123 patients with Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder that almost exclusively affects girls. It is caused by mutations in the MECP2 gene that encodes the methyl-CpG-binding protein 2 (MeCP2). In this study we correlated mutation type and location with the severity of the phenotype in 123 girls with RTT. The ability to sit, walk, speak, hand function, head growth, occurrence of epilepsy and a combined severity score were assessed in all girls at 5 years of age and then statistically correlated with the results of the molecular genetic tests. We found that patients who carry either missense mutations or deletions located within the hotspot for deletions, an area between the base pairs (bp) 1030 and 1207 of the MECP2 gene, present with a milder phenotype than other patients. We correlated the location of the mutations with the phenotype and found that all mutations that lead to either a complete or partial truncation of the region coding for the nuclear localisation signal (NLS) are associated with a more severe phenotype than other truncating mutations (p = 0.001). We did not find a significant difference between the patients with mutations in the methyl-CpG-binding domain (MBD) and those with mutations in the transcriptional repression domain (TRD). We conclude that mutation type and location correlate with the phenotype in Rett syndrome. All mutations that impair the nuclear localisation signal (NLS) are associated with more severe phenotypes.

Binding Sites↗
PubMed1993

Transcriptional analysis and regulation of the sfa determinant coding for S fimbriae of pathogenic Escherichia coli strains.

The sfa determinant codes for S fimbrial adhesins which constitute adherence factors of pathogenic Escherichia coli strains. We have recently shown that the sfa determinant is transcribed from three promoters, pA, pB, and pC. In comparison with the promoters pB and pC, promoter pA, which is located in front of the structural gene sfaA, showed very weak activity. Here we have determined the exact positions of the mRNA start points by primer extension studies. We have also shown that mRNAs of 500, 700 and 1400 bases can be detected using oligonucleotide probes specific for the genes sfaB, sfaC and sfaA. SfaB and SfaC are positive regulators influencing fimbriation and the production of the S-specific adhesin which is encoded by the gene sfaS located in the distal half of the determinant. In addition, it is demonstrated that SfaB and SfaC interfere with the regulatory effect of the histone-like protein H-NS, encoded by a locus termed drdX or osmZ. In a drdX+ strain the regulators are necessary for transcription of the sfa determinant. In contrast, sfa expression is activator-independent in a drdX- strain. In this latter genetic background, a substantial fraction of the sfa transcripts is initiated from promoter pA. On the basis of these data we discuss a model for the regulation of this adhesin-specific determinant.

Adhesins, Escherichia coli↗
PubMedDate not supplied

Large-scale quantitative proteomic study of PUMA-induced apoptosis using two-dimensional liquid chromatography-mass spectrometry coupled with amino acid-coded mass tagging.

By coupling two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS) with amino acid-coded mass tagging (AACT), we have greatly increased the analytical throughput and sequence coverage of MS-based methods for proteome-wide quantitation. The dynamic range and reproducibility of this 2D-LC-AACT quantitative approach were evaluated by profiling the mixtures with different ratios of E. coli cells grown in either regular or AACT medium. A SQL-based high thoughput MASCOT data analysis tool was developed for proteomic data sorting and mining. We investigated the early stage of apoptosis by inducing the p53 upregulated modulator of apoptosis (PUMA) through the analyses of the relative ratios of the pairwise isotope signals that were originated from the control and labeled PUMA-induced cells. In 20-hour 2D-LC-MS/MS run, 480 proteins were conclusively identified, and more than half of them were quantified. A noteworthy change in the quantitative profile was that histones and a ubiquitin conjugate protein UBC9, which are involved in DNA double-strand break (DSB) repair were significantly down-regulated in the PUMA-overexpressing apoptotic cells, suggesting the detection of DSB in the apoptotic process. The quantitative profiling efficiency of this approach was compared with the gel-based quantitative analysis scheme.

Amino Acids↗
PubMed1990

The CHL 1 (CTF 1) gene product of Saccharomyces cerevisiae is important for chromosome transmission and normal cell cycle progression in G2/M.

We have analyzed the CTF1 gene, identified in a screen for mutants with decreased chromosome transmission fidelity and shown to correspond to the previously identified chl1 mutation. Chl1 null mutants exhibited a 200-fold increase in the rate of chromosome III missegregation per cell division, and near wild-type rates of marker homozygosis on this chromosome by mitotic recombination. Analysis of the segregation of a marker chromosome indicated that sister chromatid loss (1:0 segregation) and sister chromatid non-disjunction (2:0 segregation) contributed equally to chromosome missegregation. A genomic clone of CHL1 was isolated and used to map its physical position on chromosome XVI. Nucleotide sequence analysis of CHL1 revealed a 2.6 kb open reading frame with a 99 kd predicted protein sequence that contained two PEST sequences and was 23% identical to the coding region of a nucleotide excision repair gene, RAD3. Domains of homology between these two predicted protein sequences included a helix-turn-helix motif and an ATP binding site containing a helicase consensus. Mutants lacking the CHL1 gene product are viable and display two striking, and perhaps interrelated, phenotypes: extreme chromosome instability and a delay in cell cycle progression in G2/M. This delay is independent of the cell cycle checkpoint that requires the function of the RAD9 gene.

Alleles↗
PubMed1998

Autoreactivity of human VH domains from cDNA libraries: analysis with a bacterial expression system.

Previous studies showed that VH domains of several anti-DNA Abs can bind DNA in the absence of VL. In the current work, we tested the VH autoreactive potential more generally, examining VH domains that did not come from known autoantibodies. Using a bacterial expression system, we produced 11 fusion proteins, each containing a VH domain and a B domain of staphylococcal protein A. The VH domains were coded in cDNA libraries from circulating B cells of healthy young adult humans. Thus, binding properties of the Ig molecules from which they came were unknown. The B cells had not been stimulated in vitro. Seven cDNA clones combined the frequently expressed VH3-23 gene segment with varied DH and JH segments. The other clones contained unmutated VH3-7, VH3-9, VH3-53, and VH4-39 segments. We compared these bacterial expression products with single-chain Fv, VH and VL domains of IgM mAb 18/2, a VH3-23-encoded, DNA-binding autoantibody. Submicromolar concentrations of 5 of the 11 VH domains bound to ssDNA. Those and one more also bound to immobilized poly(dT), and two bound to circular plasmid dsDNA. Soluble poly(dT) was the most potent inhibitor in competitive ELISA. Seven of the VH domains also bound to immobilized nuclear ribonucleoprotein, four to histone and none to thyroglobulin. Two interacted with the matrix of a Sephacryl S-100 column. The polyreactive autoantigen-binding properties of these VH domains raise the question of whether these properties may play a role in the formation of the VH repertoire of circulating B cells.

Amino Acid Sequence↗
PubMed2005

Intimate relationship between the genes of two transcriptional coactivators, ADA2a and PIMT, of Drosophila.

PIMT, a transcriptional coactivator which interacts with and enhances nuclear receptor coactivator PRIP function, was identified recently in mammalian cells and suggested to function as a link between two major multiprotein complexes anchored by CBP/p300 and PBP. Here we describe that the gene of the Drosophila homologue of PIMT, designated as Dtl, is closely associated and has an overlapping promoter with a gene encoding another transcriptional coactivator, ADA2a, which in turn participates in GCN5 HAT-containing complexes. Ada2a also produces an RNA polII subunit, RPB4, via alternative splicing; consequently, an overlapping regulatory region serves for the production of three proteins, each involved in transcription. By studying expression of reporter gene fusions in tissue culture cells and transgenic animals we have demonstrated that the regulatory regions of Ada2a/Rpb4 and Dtl overlap and the Dtl promoter is partly within the Ada2a/Rpb4 coding region. The shared regulatory region contains a DRE element, binding site of DREF, the protein factor involved in the regulation of a number of genes which play a role in DNA replication and cell proliferation. Despite the perfectly symmetrical DRE, DREF seems to have a more decisive role in Ada2a/Rpb4 transcription than in the transcription of Dtl.

Acetyltransferases↗
PubMed1999

Testis-specific murine centrin, Cetn1: genomic characterization and evidence for retroposition of a gene encoding a centrosome protein.

Centrin is a centrosome component in species from yeast to humans. Here, the mouse centrin 1 gene (Cetn1) is analyzed with respect to its genomic structure, chromosome localization, tissue-specific expression, and phylogenetic relationship to the other mouse centrin genes and their human orthologs. Cetn1 is an intronless gene located on chromosome 18A2 that encodes a 172-amino-acid protein with a predicted molecular mass of 19,696 Da (pI 4.61) and all of the structural features common to centrin. Cetn1 possesses the sequence features of an expressed retroposon: the gene lacks introns, the open reading frame is not interrupted by stop codons, and the coding region is flanked by a pair of direct repeats. Reverse transcriptase-polymerase chain reaction and Northern blot analysis demonstrate that Cetn1 expression is limited exclusively to the testis in adult male mice. Cetn1 expression is first seen in the neonatal testis at 14 days postpartum, reaching adult levels by day 17. These observations provide new insight into the regulation, function, and evolutionary history of centrin in higher eukaryotes.

Amino Acid Sequence↗
PubMed1988

Nucleotide sequence of a cDNA clone encoding mouse transition protein 1.

We have determined the nucleotide sequence of cDNA clones encoding mouse transition protein 1 (TP1), a basic nuclear protein involved in nuclear condensation during spermiogenesis. The nucleotide sequence predicts that transition protein 1 in rats and mice differs by only one amino acid. The rate of substitution of nucleotides in the coding region of mouse and rat transition protein 1 mRNA is close to the average of many proteins in rats and mice, and the usage of degenerate codons is typical of the mouse. The identification of this cDNA clone, in conjunction with previous work (Kleene et al. (1983) Dev. Biol. 98, 455-464; Hecht et al. (1986) Exp. Cell Res. 164, 183-190), demonstrates that the mRNA for mouse transition protein 1 accumulates during the haploid phase of spermatogenesis.

Animals↗
PubMed2001

The Arabidopsis thaliana genome contains at least 29 active genes encoding SET domain proteins that can be assigned to four evolutionarily conserved classes.

SET domains are conserved amino acid motifs present in chromosomal proteins that function in epigenetic control of gene expression. These proteins can be divided into four classes as typified by their Drosophila members E(Z), TRX, ASH1 and SU(VAR)3-9. Homologs of all four classes have been identified in yeast and mammals, but not in plants. A BLASTP screening of the Arabidopsis genome identified 37 genes: three E(z) homologs, five trx homologs, four ash1 homologs and 15 genes similar to Su(var)3-9. Seven genes were assigned as trx-related and three as ash1-related. Only four genes have been described previously. Our classification is based on the characteristics of the SET domains, cysteine-rich regions and additional conserved domains, including a novel YGD domain. RT-PCR analysis, cDNA cloning and matching ESTs show that at least 29 of the genes are active in diverse tissues. The high number of SET domain genes, possibly involved in epigenetic control of gene activity during plant development, can partly be explained by extensive genome duplication in Arabidopsis. Additionally, the lack of introns in the coding region of eight SU(VAR)3-9 class genes indicates evolution of new genes by retrotransposition. The identification of putative nuclear localization signals and AT-hooks in many of the proteins supports an anticipated nuclear localization, which was demonstrated for selected proteins.

Active Transport, Cell Nucleus↗
PubMed2000

Frequent frameshift mutations of RIZ in sporadic gastrointestinal and endometrial carcinomas with microsatellite instability.

Many lines of evidence suggest that the retinoblastoma protein interacting zinc finger gene RIZ is a strong candidate for the tumor suppressor locus on 1p36, a region commonly deleted in many human cancers with chromosomal instability. In addition, a role for RIZ in tumors of the microsatellite instability pathway is suggested by frequent frameshift mutations in hereditary non-polyposis colorectal carcinomas. Here we studied RIZ mutations in sporadic cancers with microsatellite instability. Frameshift mutations in the two coding polyadenosine tracks of RIZ were found in 19 (48%) of 40 gastric carcinomas, 6 (33%) of 18 endometrial carcinomas, 14 (26%) of 51 of colorectal carcinomas, and 7 (54%) of 13 cell lines. Eleven tumor tissues showed biallelic inactivation of RIZ. In contrast, no frameshift mutations were found in 70 microsatellite stable tumors. These results suggest an important role for RIZ in sporadic cancers with microsatellite instability.

Alleles↗
PubMed1993

Chromatin structures and transcription of rDNA in yeast Saccharomyces cerevisiae.

The chromatin structure of yeast ribosomal DNA was analyzed in vivo by crosslinking intact cells with psoralen. We found that in exponentially growing cultures the regions coding for the 35S rRNA precursor fall into two distinct classes. One class was highly accessible to psoralen and associated with nascent RNAs, characteristic for transcriptionally active rRNA genes devoid of nucleosomes, whereas the other class showed a crosslinking pattern indistinguishable from that of bulk chromatin and was interpreted to represent the inactive rRNA gene copies. By crosslinking the same strain growing in complex or minimal medium, we have shown that yeast cells can modulate the proportion of active (non-nucleosomal) and inactive (nucleosomal) rRNA gene copies in response to variations in environmental conditions which suggests that yeast can regulate rRNA synthesis by varying the number of active gene copies, in contrast to the vertebrate cells studied so far. Whereas intergenic spacers flanking inactive rRNA gene copies are packaged in a regular nucleosomal array, spacers flanking active genes show an unusual crosslinking pattern suggesting a complex interaction of regulatory factors and histones with DNA.

Chromatin↗
PubMed1984

Isolation and partial sequence of bovine cDNA clones for the high-mobility-group protein (HMG-1).

Several cloned ds cDNAs containing bovine HMG-1 sequences have been isolated from a ds cDNA library prepared from the poly(A)+ mRNA fraction of bovine testis using a pool of synthetic 17-meric oligo-deoxyribonucleotides with the sequence 5'-GTAGTTAGTTCCACATTCTC-3' selected to be complementary to a region of the coding sequence corresponding to the relatively unambiguous amino acid sequence, Glu-Met-Trp-Asn-Asn-Thr. Determination of the DNA sequences in these clones indicates that they represent the 3' half of the HMG-1 message and contain an unusually long putative 3' untranslated region of 480 nucleotides. The sequence of the coding region corresponding to the 99 amino acids at the C-terminus of HMG-1 has been determined and largely confirms the published primary sequence in this region (Walker JM, (1982) in: The HMG Chromosomal Proteins, Academic Press, London & New York, pp. 69-88). In addition the cDNA sequence provides a complete sequence of the 30 residue polyacidic region and shows that the nucleotide sequence in this region is a repeating one and that the polyacidic domain comprises the C-terminus of the protein.

Amino Acid Sequence↗
PubMed1995

Identification and characterization of a novel family of serine/threonine kinases containing two N-terminal LIM motifs.

We previously isolated human cDNA coding for LIMK1 (LIM motif-containing protein kinase-1), a putative protein kinase containing two LIM motifs at the N terminus and an unusual protein kinase domain at the C terminus. In the present study, we isolated human cDNA encoding LIMK2, a second member of a LIMK family, with a domain structure similar to LIMK1 and 50% overall amino acid identity with LIMK1. The protein kinase domains of LIMK1 and LIMK2 are unique in that they contain an unusual sequence motif Asp-Leu-Asn-Ser-His-Asn in subdomain VIB and a highly basic insert between subdomains VII and VIII. Expression patterns of LIMK1 and LIMK2 mRNAs in human tissues differ significantly. Chromosomal localization of human LIMK1 and LIMK2 genes was assigned to 7q11.23 and 22q12, respectively, by fluorescence in situ hybridization. The Myc epitope-tagged LIMK1 and LIMK2 proteins transiently expressed in COS cells exhibited serine/threonine-specific kinase activity toward myelin basic protein and histone in in vitro kinase assay. Immunofluorescence and subcellular fractionation analysis revealed that Myc-tagged LIMK1 and LIMK2 were localized mainly in the cytoplasm. The "native" LIMK1 protein endogenously expressed in A431 epidermoid carcinoma cells also exhibited serine/threonine kinase activity. The specific activity of native LIMK1 from A431 cells was apparently much higher than that of "recombinant" LIMK1 ectopically expressed in COS cells, hence, it is likely that there is a mechanism, by which native LIMK1 is activated. A 140-kDa tyrosine-phosphorylated protein (pp140) was co-immunoprecipitated with native LIMK1 form A431 cell lysates; therefore, pp140 may be a LIMK1-associated protein involved in the regulation of LIMK1 function.

Amino Acid Sequence↗
PubMed2005

Lack of germ-line mutations at the specific BRCA1-IRIS coding sequence in 114 Spanish high-risk breast/ovarian families.

A new BRCA1 locus product called BRCA1-IRIS has been identified recently. High-risk breast/ovarian families have not been screened for germ-line mutations at the specific BRCA1-IRIS coding sequence, as it was considered merely as part of BRCA1 intron 11. Here we report the first comprehensive screening of germ-line mutations in a cohort of 116 index cases from high-risk breast/ovarian families in which no germ-line mutation was identified in BRCA1 or BRCA2. We did not find germ-line mutations at the specific BRCA1-IRIS coding sequence in any sample. The only heterozygous patter identified by DGGE was caused by a C to A substitution in the non-coding 3' sequence, 123 bases downstream of the BRCA1-IRIS stop codon (IVS11+268C/A). The data indicates that it is probably a neutral change not associated with cancer risk. Our analysis suggests that the role of germ-line mutations at the specific BRCA1-IRIS sequence in breast cancer susceptibility, if any, is marginal and do not explain a significant fraction of high-risk breast/ovarian families, at least in the population analyzed.

BRCA1 Protein↗
PubMed1992

Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias.

We have identified a human homolog of the Drosophila trithorax protein that is structurally altered by 11q23 translocations in acute leukemias. Human trithorax (HRX) is a predicted 431 kd protein containing two potential DNA-binding motifs consisting of zinc fingers conserved with the fly protein and nonconserved amino-terminal "AT hook" motifs related to the DNA-binding motifs in HMG proteins. 11q23 translocations disrupt the HRX gene between these two motifs, and in a t(11;19)-carrying cell line fusion transcripts are expressed from both derivative chromosomes. The more abundant derivative 11 transcript codes for a chimeric protein containing the AT hook motifs fused to a previously undescribed protein (ENL) from chromosome 19. These data suggest a novel role for a trithorax-homologous protein in multilineage human leukemias that may be mediated by DNA binding within the minor groove at AT-rich sites, implicated to play an important role in bacterial IHF-, yeast datin-, and mammalian HMG-mediated gene activation.

Acute Disease↗