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At least 343 records · Page 19Linked to original sources
PubMed2000

Alterations of H19 imprinting and IGF2 replication timing are infrequent in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder resulting from dysregulation of multiple imprinted genes through a variety of distinct mechanisms. A frequent alteration in BWS involves changes in the imprinting status of the coordinately regulated IGF2 and H19 genes on 11p15. Patients have been categorized according to alterations in the imprinted expression, allele-specific methylation, and regional replication timing of these genes. In this work, IGF2/H19 expression, H19 DNA methylation, and IGF2 regional replication timing were studied in nine karyotypically normal BWS fibroblasts and two BWS patients with maternally inherited 11p15 chromosomal rearrangements. Informative patients (9/9) maintained normal monoallelic H19 expression/methylation, despite biallelic IGF2 expression in 6/9. Replication timing studies revealed no changes in the pattern of asynchronous replication timing for both a patient with biallelic IGF2 expression and a patient carrying an 11p15 inversion. In contrast, a patient with a chromosome 11;22 translocation and normal H19 expression/methylation exhibited partial loss of asynchrony and a shift toward earlier replication times. These results indicate that in BWS, (1) H19 imprinting alterations are less frequent than previously estimated, (2) IGF2 imprinting and H19 imprinting are not necessarily coordinated, and (3) alterations in regional replication timing are generally not correlated with either chromosomal rearrangements or the imprinting status of IGF2 and H19.

Beckwith-Wiedemann Syndrome↗
PubMed2001

Low-copy-number human transgene is recognized as an X inactivation center in mouse ES cells, but fails to induce cis-inactivation in chimeric mice.

X chromosome inactivation is initiated from a segment of the mammalian X chromosome called the X inactivation center. Transgenes from this region of the murine X chromosome are providing the means to identify the DNA needed for cis inactivation in mice. We recently showed that chimeric mice carrying transgenes from the human X inactivation center (XIC) region also provide a functional assay for human XIC activity; approximately 6 copies of a 480-kb human transgene (ES-10) were sufficient to initiate random X inactivation in cells of male chimeric mice (Migeon et al., 1999, Genomics, 59, 113-121). Now, we report studies of another human transgene (ES-5), which contains less than 300 kb of the human XIC region on Xq13.2 including an intact XIST locus and which has inserted in one or two copies into mouse chromosome 6. The ES-5 transgene is recognized as an X inactivation center in mouse embryonic stem cells, but is not sufficient to induce random X inactivation in somatic cells of highly chimeric mice. Human transgenes in chimeric mice provide a means to uncouple the key steps in this complex pathway and facilitate the search for essential components of the human XIC region.

Animals↗
PubMed2001

Elucidation of the minimal sequence required to imprint H19 transgenes.

The imprinted mouse H19 gene exhibits maternal allele-specific expression and paternal allele-specific hypermethylation. We previously demonstrated that a 14-kb H19 minitransgene possessing 5' differentially methylated sequence recapitulates the endogenous H19 imprinting pattern when present as high-copy arrays. To investigate the minimal sequences that are sufficient for H19 transgene imprinting, we have tested new transgenes in mice. While transgenes harboring limited or no 3' H19 sequence indicate that multiple elements within the 8-kb 3' fragment are required for appropriate imprinting, transgenes incorporating 1.7 kb of additional 5' sequence mimic the endogenous H19 pattern, including proper imprinting of low-copy arrays. One of these imprinted lines had a single 15.7-kb transgene integrant. This is the smallest H19 transgene identified thus far to display imprinting properties characteristic of the endogenous gene, suggesting that all cis-acting elements required for H19 imprinting in endodermal tissues reside within the 15.7-kb transgenic sequence.

Alleles↗
PubMed2001

A complex duplication created by gene targeting at the imprinted H19 locus results in two classes of methylation and correlated Igf2 expression phenotypes.

Imprinting of the mouse H19 and Igf2 genes is dependent on the presence of an intervening imprinting control region (ICR) situated 2 kb upstream of H19 and approximately 70 kb downstream of Igf2. Several recent studies have provided substantial evidence that the unmethylated maternal ICR acts as an insulator that prevents activation of Igf2 by a suite of enhancers downstream of the H19 gene. The methylated paternal ICR and H19 promoter have no activity, allowing sole activation of Igf2 expression. We have produced mice in which a duplication of the H19/Igf2 ICR produces, in each generation, two classes of methylation levels that correlated with two Igf2 imprinting phenotypes. One hypermethylated class also shows activation of the normally silent Igf2 gene, whereas the other hypomethylated class shows only slight activation of Igf2, in agreement with methylation's role in ICR function. This study describes a rare, possibly unique type of mutation that induces two distinct phenotypes in each generation.

Alleles↗
PubMed2001

Imprinting status of 11p15 genes in Beckwith-Wiedemann syndrome patients with CDKN1C mutations.

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by somatic overgrowth, congenital malformations, and predisposition to childhood tumors. Aberrant expression of multiple imprinted genes, including H19, IGF2, KCNQ1OT1, and CDKN1C, has been observed in BWS patients. It has been estimated that mutations in CDKN1C occur in 12-17% of BWS patients. We have screened 10 autosomal dominant pedigrees and 65 sporadic BWS cases by PCR/heteroduplex analysis and DNA sequencing and have identified four mutations, two of which were associated with biallelic IGF2 expression and normal H19 and KCNQ1OT1 imprinting. One patient demonstrated phenotypic expression of paternally transmitted mutation in this maternally expressed gene, a second proband is the child of one of a pair of monozygotic twin females who carry the mutation de novo, and a third patient exhibited unusual skeletal changes more commonly found in other overgrowth syndromes. When considered with other studies published to date, this work reveals the frequency of CDKN1C mutations in BWS to be only 4.9%. This is the first report of an analysis of the imprinting status of genes in the 11p15 region where CDKN1C mutations were associated with loss of IGF2 imprinting and maintenance of H19 and KCNQ1OT1 imprinting.

Amino Acid Sequence↗
PubMed1999

Expression and imprinting of insulin-like growth factor II (IGF2) and H19 genes in uterine leiomyomas.

Genomic imprinting is defined as a gamete of origin-specific epigenetic modification of DNA leading to differential gene expression in the zygote. Several imprinted genes have been identified and some of them are associated with tumor development. We investigated the expression and the imprinting status of IGF2 and H19 genes in 47 uterine leiomyomas. Using allelic transcription assay, we detected the expression of the IGF2 gene in 10 of a total of 15 informative cases. No loss of imprinting, as determined by the finding of biallelic expression, was detected in any case. The expression of H19 gene was detected in 10 of 20 informative cases and the imprinting pattern was also maintained in all of them. Our data suggest that alterations in IGF2 and H19 genes expression by loss of imprinting do not occur in uterine leiomyomas.

Adult↗
PubMed1996

Recent amplification of rat ID sequences.

The rodent identifier (ID) family of repeats has amplified at an extremely high rate in the rat genome in recent evolutionary time, resulting in 130,000 copies per haploid genome. Statistical analyses support the grouping of 119 individual rat ID elements into four major and three minor subfamilies based on six diagnostic nucleotide positions. The consensus sequence of the oldest subfamily is identical to the ID region of the rat BC1 RNA gene, suggesting that the BC1 gene has dominated the early amplification of rat ID elements. The other six subfamilies share at least one diagnostic mutation in relation to the BC1 gene and show much less nucleotide sequence divergence, indicating that the recent large amplification of rat ID elements has been driven by another lineage of master gene(s) in the rat genome. This is consistent with the formation of a new lineage of master elements for ID amplification in rat. The formation of most rat ID elements appears to have occurred during the past three million years based on the results that four out of five randomly chosen ID elements are present only in the genome of one rat species and not in other closely related species.

Animals↗
PubMed2000

An unexpected affected female patient in a classical Lesch-Nyhan family.

Lesch-Nyhan disease is a genetic disorder of purine metabolism caused by defective activity of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT), resulting from mutation in the corresponding gene on the long arm of the X chromosome (Xq26). The classical phenotype, which includes spasticity, involuntary movements, developmental disability, and self-injurious behavior, occurs exclusively in males, while heterozygous, carrier females are clinically normal. We analyzed an Argentine family in which there were male and female siblings with clinically identical classic features of Lesch-Nyhan disease. The mother and an older daughter were carriers and had normal phenotypes. We identified the HPRT mutation in the family. It is a C --> T transition at position 508 of the cDNA (c.508 C --> T) that changes the CGA codon for Arg(169) to the TGA stop codon (R169X). The female patient was karyotypically normal and heterozygous for the mutation. She inherited the HPRT mutation from her mother, but she also had unexpected nonrandom inactivation of the paternal X chromosome carrying the normal HPRT gene. This additional genetic alteration is the cause of the clinical expression of disease in this female patient.

Adult↗
PubMed2005

Chromatin modifications on the inactive X chromosome.

In female mammals, one X chromosome is transcriptionally silenced to achieve dosage compensation between XX females and XY males. This process, known as X-inactivation, occurs early in development, such that one X chromosome is silenced in every cell. Once X-inactivation has occurred, the inactive X chromosome is marked by a unique set of epigenetic features that distinguishes it from the active X chromosome and autosomes. These modifications appear sequentially during the transition from a transcriptionally active to an inactive state and, once established, act redundantly to maintain transcriptional silencing. In this review, we survey the unique epigenetic features that characterize the inactive X chromosome, describe the mechanisms by which these marks are established and maintained, and discuss how each contributes to silencing the inactive X chromosome.

Animals↗
PubMed2003

Imprinting.

Explore the source record for details and available documents.

Alleles↗
PubMed1994

Comparison of soybean and pea ENOD40 cDNA clones representing genes expressed during both early and late stages of nodule development.

A pea cDNA clone representing the homologue of the soybean pGmENOD40-1 was isolated and characterized. At the nucleotide level both clones share 55% homology. Strikingly, the homology between the polypeptides derived from the pea and soybean ENOD40 cDNA sequences is only 14%. Despite this low homology Southern analyses revealed that the isolated pea cDNA clone represents the single pea ENOD40. In situ hybridizations showed that at early stages of nodule development and in mature nodules the expression pattern of pea ENOD40 is comparable to that of soybean ENOD40. Although ENOD40 show similar expression patterns in these two nodules, it is questionable whether the putative polypeptides have a similar function, since the homology is very low.

Amino Acid Sequence↗
PubMed1996

Phaseolus ENOD40 is involved in symbiotic and non-symbiotic organogenetic processes: expression during nodule and lateral root development.

ENOD40 is an early nodulin gene, recently isolated from legume species forming nodules either after Rhizobium infection or spontaneously. ENOD40 cDNAs from Phaseolus plants were isolated and nucleotide sequence determination revealed 85% and 88.5% homology with the reported soybean cDNA clones. The putative polypeptide deduced coincides with the soybean one but a stop codon, almost in the middle of the respective ORF, renders it much shorter. This polypeptide was overexpressed as a fusion protein in Escherichia coli. Although the spatial expression pattern of the gene in the root pericycle and nodule primordium at early stages of development as well as in the pericycle of the vascular bundles and uninfected cells in mature nodules is comparable to the gene's expression pattern in soybean, differences in developmental regulation are evident. We have shown that ENOD40 transcripts are also detected at very early stages of lateral root development, in the dividing pericycle cells of the root stele that give rise to the lateral root primordia. The presence of Rhizobium causes an enhancement of the gene's expression and also induction of the gene in the vascular tissues of developed lateral roots. Interestingly, a discrimination on the gene's expression level in adventious and acropetal incipient lateral root primordia, emerging in infected and uninfected roots, is observed. This indicates that the gene's product may be involved in the hormonal status of the plant and that ENOD40 may be used as a molecular marker in lateral root initiation.

Amino Acid Sequence↗
PubMed1993

A novel coding sequence belonging to a new multicopy gene family mapping within the human MHC class I region.

The human major histocompatibility complex (MHC) region is a genomic region spanning about 4000 kilobases (kb) including the class I, class II, and class III subregions. The class I subregion is larger than the two others but with fewer genes described to date. It includes a) classical human leucocyte antigen (HLA) class I genes (HLA-A, HLA-B, HLA-C) which are highly polymorphic and encode products presenting the endogenous antigenic peptides to the T-cell receptors, and b) non-classical class I genes (HLA-E, HLA-F, HLA-G) whose function is still unknown. In this study, we describe the first coding sequence which is not structurally related to the class I genes, although it is localized within the MHC class I region. This novel gene, P5-1, belongs to a multiple copy family, all members of which map within the MHC. Although the P5-1 sequence showed no similarity to sequences in different databanks, its transcription, which is restricted to lymphoid tissues, argues for an immunological function of its product.

Amino Acid Sequence↗
PubMed1994

Non-homologous recombination within the major histocompatibility complex creates a transcribed hybrid sequence.

The P5-1 cDNA clone maps to the human MHC class I region (Vernet et al. 1993a). In this paper, we show that the P5-1 cDNA represents a chimeric transcript in which the first exon of an MHC class I gene has been spliced to an unrelated sequence. The corresponding gene P5-1 is composed of the 5' sequence of an MHC class I gene including the promoter region, the first exon, and the half of the first intron fused to an unrelated intron, followed by a large exon. Furthermore, the non-class I part of P5-1 is present within the MHC class I region in multiple copies, defining the P5 family. Another member of the P5 family is fused to a class I gene, although by a type of rearrangement different from P5-1. These two fusion events between members of HLA class I and P5 families reflect the existence of a duplication unit including two class I genes and a P5 sequence. These data shed light on the MHC class I evolution and on the creation and evolution of new genes.

Base Sequence↗
PubMed1995

The orientation of gene maps by recombination of flanking markers for the am locus of Neurospora crassa.

Fincham (1967), Smyth (1973 b) and Rambosek and Kinsey (1983) have each generated fine-structure maps of the am gene of Neurospora crassa. Each map had a consistent linear order of alleles but the assignment of an orientation with respect to other linkage group-V loci differed. Fincham found the end marked by the am6 allele to be at the distal end of the locus, Smyth found am6 to be at the proximal end while the data of Rambosek and Kinsey did not suggest an orientation. Smyth s orientation has been adopted as the standard, but not unreservedly. We have aligned the genetic and physical maps of the am gene, showing that am6 is at the distal end, supporting Fincham's orientation. However, we suggest that an assumption used to orient fine structure genetic maps is flawed and that the conflicting orientation between these three studies follows from the different choice of flanking markers.

Chromosome Mapping↗