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A Bird

Publications and source records attributed to A Bird.

At least 37 records · Page 2Linked to original sources
PubMed2001

A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome.

Rett syndrome (RTT) is an inherited neurodevelopmental disorder of females that occurs once in 10,000-15,000 births. Affected females develop normally for 6-18 months, but then lose voluntary movements, including speech and hand skills. Most RTT patients are heterozygous for mutations in the X-linked gene MECP2 (refs. 3-12), encoding a protein that binds to methylated sites in genomic DNA and facilitates gene silencing. Previous work with Mecp2-null embryonic stem cells indicated that MeCP2 is essential for mouse embryogenesis. Here we generate mice lacking Mecp2 using Cre-loxP technology. Both Mecp2-null mice and mice in which Mecp2 was deleted in brain showed severe neurological symptoms at approximately six weeks of age. Compensation for absence of MeCP2 in other tissues by MeCP1 (refs. 19,20) was not apparent in genetic or biochemical tests. After several months, heterozygous female mice also showed behavioral symptoms. The overlapping delay before symptom onset in humans and mice, despite their profoundly different rates of development, raises the possibility that stability of brain function, not brain development per se, is compromised by the absence of MeCP2.

Animals↗
PubMed2001

The ageing macula.

Explore the source record for details and available documents.

Genetic Predisposition to Disease↗
PubMed2000

Mapping the DNA binding domain of the Zap1 zinc-responsive transcriptional activator.

The Zap1 transcriptional activator of Saccharomyces cerevisiae plays a major role in zinc homeostasis by inducing the expression of several genes under zinc-limited growth conditions. This activation of gene expression is mediated by binding of the protein to one or more zinc-responsive elements present in the promoters of its target genes. To better understand how Zap1 functions, we mapped its DNA binding domain using a combined in vivo and in vitro approach. Our results show that the Zap1 DNA binding domain maps to the carboxyl-terminal 194 amino acids of the protein; this region contains five of its seven potential zinc finger domains. Fusing this region to the Gal4 activation domain complemented a zap1Delta mutation for low zinc growth and also conferred high level expression on a zinc-responsive element-lacZ reporter. In vitro, the purified 194-residue fragment bound to DNA with a high affinity (dissociation constant in the low nanomolar range) similar to that of longer fragments of Zap1. Furthermore, by deletion and site-directed mutagenesis, we demonstrated that each of the five carboxyl-terminal zinc fingers are required for high affinity DNA binding.

Amino Acid Sequence↗
PubMed2000

Histone deacetylases: silencers for hire.

Over the past few years, the long-standing idea that covalent modification of chromatin can play a role in determining states of gene activity has been confirmed. Eukaryotic genes can be silenced by deacetylation of acetyl-lysine moieties in the N-terminal tails of histones. Recent work links histone deacetylases with an increasing number of repressors, suggesting that deacetylation might be a rather pervasive feature of transcriptional repression systems.

Animals↗
PubMed2000

Sequence analysis of transposable elements in the sea squirt, Ciona intestinalis.

A systematic search of 1 Mb of genomic sequences from the sea squirt, Ciona intestinalis, revealed the presence of six families of transposable elements. The Cigr-1 retrotransposon contains identical 245-bp long terminal repeats (LTRs) and a 3,630-bp open reading frame (ORF) encoding translation products in the same order as the domains characteristic of gypsy/Ty3-type LTR retrotransposons. The closest homologs of the reverse transcriptase domain were in gypsy elements from Drosophila and the sushi element from the pufferfish. However, the capsid-nucleocapsid region shows the clearest homology to an echinoderm element, Tgr1. Database searches also indicated two classes of non-LTR retrotransposon, named Cili-1 and Cili-2. The Cili-1 sequences show matches to regions of the ORF2 product of mammalian L1 elements. The Cili-2 sequences possess similarity to the RNaseH domain of Lian-Aa1, a mosquito non-LTR retrotransposon. The most abundant element was a short interspersed nucleotide element named Cics-1 with a copy number estimated at 40,000. Cics-1 consists of two conserved domains separated by an A-rich stretch. The 172-bp 5' domain is related to tRNA sequences, whereas the 110-bp 3' domain is unique. Cics-1 is unusual, not just in its modular structure, but also in its lack of a 3' poly(A) tail or direct flanking repeats. A second abundant element, Cimi-1, has an A+T-rich 193-bp consensus sequence and 30-bp terminal inverted repeats (TIRs) and is usually flanked by A+T-rich 2-4-bp putative target site duplications-characteristics of miniature inverted-repeat transposable elements found in plants and insects. A single 2,444-bp foldback element was found, possessing long TIRs containing an A+T-rich internal domain, an array of subrepeats, and a flanking domain at the TIR ends; this is the first example of a chordate foldback element. This study provides the first systematic characterization of the families of transposable elements in a lower chordate.

Amino Acid Sequence↗
PubMed2000

Active repression of methylated genes by the chromosomal protein MBD1.

MBD1 belongs to a family of mammalian proteins that share a methyl-CpG binding domain. Previous work has shown that MBD1 binds to methylated sites in vivo and in vitro and can repress transcription from methylated templates in transcription extracts and in cultured cells. In the present study we established by several experimental criteria that, contrary to a previous report, MBD1 is not a component of the MeCP1 repressor complex. We identified a powerful transcriptional repression domain (TRD) at the C terminus of MBD1 that can actively repress transcription at a distance. Methylation-dependent repression in vivo depends on the presence of both the TRD and the methyl-CpG binding domain. The mechanism is likely to involve deacetylation, since the deacetylase inhibitor trichostatin A can overcome MBD1-mediated repression. Accordingly, we found that endogenous MBD1 is particularly concentrated at sites of centromeric heterochromatin, where acetylated histone H4 is deficient. Unlike MBD2 and MeCP2, MBD1 is not depleted by antibodies to the histone deacetylase HDAC1. Thus, the deacetylase-dependent pathway by which MBD1 actively silences methylated genes is likely to be different from that utilized by the methylation-dependent repressors MeCP1 and MeCP2.

Acetylation↗
PubMed2000

An analysis of ABCR mutations in British patients with recessive retinal dystrophies.

PURPOSE: Several reports have shown that mutations in the ABCR gene can lead to Stargardt disease (STGD)/fundus flavimaculatus (FFM), autosomal recessive retinitis pigmentosa (arRP), and autosomal recessive cone-rod dystrophy (arCRD). To assess the involvement of ABCR in these retinal dystrophies, the gene was screened in a panel of 70 patients of British origin. METHODS: Fifty-six patients exhibiting the STGD/FFM phenotype, 6 with arRP, and 8 with arCRD, were screened for mutations in the 50 exons of the ABCR gene by heteroduplex analysis and direct sequencing. Microsatellite marker haplotyping was used to determine ancestry. RESULTS: In the 70 patients analyzed, 31 sequence changes were identified, of which 20 were considered to be novel mutations, in a variety of phenotypes. An identical haplotype was associated with the same pair of in-cis alterations in 5 seemingly unrelated patients and their affected siblings with STGD/FFM. Four of the aforementioned patients were found to carry three alterations in the coding sequence of the ABCR gene, with two of them being in-cis. CONCLUSIONS: These results suggest that ABCR is a relatively polymorphic gene. Because putative mutations have been identified thus far only in 25 of 70 patients, of whom only 8 are compound heterozygotes, a large number of mutations have yet to be ascertained. The disease haplotype seen in the 5 patients carrying the same "complex" allele is consistent with the presence of a common ancestor.

ATP-Binding Cassette Transporters↗
PubMed1999

Somatic frameshift mutations in the MBD4 gene of sporadic colon cancers with mismatch repair deficiency.

Defects of mismatch repair are thought to be responsible for carcinogenesis in hereditary non-polyposis colorectal cancer and about 15% of sporadic colon cancers. The phenotype is seen as microsatellite instability and is known to be caused either by mutations in mismatch repair genes or by aberrant methylation of these genes stabilizing their downregulation. Lack of repair of microsatellite sequence errors, created during replication, leads to a mutation-prone phenotype. Where mutations occur within mononucleotide tracts within exons they cause translation frameshifts, premature cessation of translation and abnormal protein expression. Such mutations have been observed in the TGFbetaRII, BAX, IGFIIR, MSH3 and MSH6 genes in colon and other cancers. We describe here frameshift mutations affecting the gene for the methyl-CpG binding thymine glycosylase, MBD4, in over 40% of microsatellite unstable sporadic colon cancers. The mutations all appear heterozygous but their location would ensure truncation of the protein between the methyl-CpG binding and glycosylase domains, thus potentially generating a dominant negative effect. It is thus possible that such mutations enhance mutation frequency at other sites in these tumours. A suggestion has been made that MBD4 (MED1) mutations may lead to an increased rate of microsatellite instability but this mechanism appears unlikely due to the nature of mutations we have found.

Base Pair Mismatch↗
PubMed1999

Densely methylated sequences that are preferentially localized at telomere-proximal regions of human chromosomes.

We have constructed a library of densely methylated DNA sequences from human blood DNA by selecting fragments with a high affinity for a methyl-CpG binding domain (MBD) column. PCR analysis of the library confirmed the presence of known densely methylated CpG island sequences. Analysis of random clones, however, showed that the library was dominated by sequences whose G+C content and CpG frequency were intermediate between those of bulk genomic DNA and bona fide CpG islands. When human chromosomes were probed with the library by fluorescent in situ hybridisation (FISH), the predominant sites of labelling were at terminal regions of many chromosomes, approximately corresponding to T-bands. Analysis of the methylation status of random clones indicated that all were heavily methylated at CpGs in blood DNA, but many were under-methylated in sperm DNA. Lack of methylation in germ cells may reduce CpG depletion at some sub-terminal sequences and result in a high density of methyl-CpG when these regions become methylated in somatic cells.

Chromosome Mapping↗
PubMed1999

Epidemiology of age-related macular degeneration.

For more than two decades, researchers have sought to identify "risk factors" for age-related macular degeneration (AMD), a major cause of irreversible vision loss in the Western world, particularly in the elderly. Two issues have complicated this search: failure to differentiate between different stages of AMD and misinterpretation of measures of association (odds ratios) and risk (risk ratios) derivable from different research designs. Fortunately, in more recent epidemiologic studies, more attention has been given to these issues. Three groups of potential "risk factors" that have been studied were reviewed: those known to be risk factors for cardiovascular disease, environmental factors, and racial and ethnic factors. Of these, only tobacco smoking, a known risk factor for cardiovascular disease, has been demonstrated to be associated with AMD consistently across many studies of different design, carried out within different populations. The available evidence supports at least a doubling of risk of late AMD associated with long-term smoking, a factor that is under the control of the individual. The preponderance of evidence has not supported other factors to the same degree. Presently, racial and ethnic factors are high priorities for further research.

Age Factors↗
PubMed1999

The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites.

In addition to its well-documented effects on gene silencing, cytosine methylation is a prominent cause of mutations. In humans, the mutation rate from 5-methylcytosine (m5C) to thymine (T) is 10-50-fold higher than other transitions and the methylated sequence CpG is consequently under-represented. Over one-third of germline point mutations associated with human genetic disease and many somatic mutations leading to cancer involve loss of CpG. The primary cause of mutability appears to be hydrolytic deamination. Cytosine deamination produces mismatched uracil (U), which can be removed by uracil glycosylase, whereas m5C deamination generates a G x T mispair that cannot be processed by this enzyme. Correction of m5CpG x TpG mismatches may instead be initiated by the thymine DNA glycosylase, TDG. Here we show that MBD4, an unrelated mammalian protein that contains a methyl-CpG binding domain, can also efficiently remove thymine or uracil from a mismatches CpG site in vitro. Furthermore, the methyl-CpG binding domain of MBD4 binds preferentially to m5CpG x TpG mismatches-the primary product of deamination at methyl-CpG. The combined specificities of binding and catalysis indicate that this enzyme may function to minimize mutation at methyl-CpG.

Amino Acid Sequence↗
PubMed1999

CpG islands as genomic footprints of promoters that are associated with replication origins.

The primary target for DNA methylation in mammalian genomes is cytosine in the dinucleotide CpG. High densities of CpG dinucleotides are found in CpG islands, but paradoxically CpG islands are normally in a non-methylated state. Here, we speculate why CpG islands are immune to methylation and why they are so rich in guanine and cytosine relative to the surrounding DNA. We propose that CpG islands are associated with promoters that are transcriptionally active at totipotent stages of development and can also act as origins of DNA replication. CpG islands may be 'footprints' caused by early DNA replication intermediates at dual function promoters of this kind.

Animals↗
PubMed1999

Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation.

ATP-dependent nucleosome remodeling and core histone acetylation and deacetylation represent mechanisms to alter nucleosome structure. NuRD is a multisubunit complex containing nucleosome remodeling and histone deacetylase activities. The histone deacetylases HDAC1 and HDAC2 and the histone binding proteins RbAp48 and RbAp46 form a core complex shared between NuRD and Sin3-histone deacetylase complexes. The histone deacetylase activity of the core complex is severely compromised. A novel polypeptide highly related to the metastasis-associated protein 1, MTA2, and the methyl-CpG-binding domain-containing protein, MBD3, were found to be subunits of the NuRD complex. MTA2 modulates the enzymatic activity of the histone deacetylase core complex. MBD3 mediates the association of MTA2 with the core histone deacetylase complex. MBD3 does not directly bind methylated DNA but is highly related to MBD2, a polypeptide that binds to methylated DNA and has been reported to possess demethylase activity. MBD2 interacts with the NuRD complex and directs the complex to methylated DNA. NuRD may provide a means of gene silencing by DNA methylation.

Adenosine Triphosphatases↗
PubMed1999

Nonmethylated transposable elements and methylated genes in a chordate genome.

The genome of the invertebrate chordate Ciona intestinalis was found to be a stable mosaic of methylated and nonmethylated domains. Multiple copies of an apparently active long terminal repeat retrotransposon and a long interspersed element are nonmethylated and a large fraction of abundant short interspersed elements are also methylation free. Genes, by contrast, are predominantly methylated. These data are incompatible with the genome defense model, which proposes that DNA methylation in animals is primarily targeted to endogenous transposable elements. Cytosine methylation in this urochordate may be preferentially directed to genes.

Animals↗