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At least 451 records · Page 25Linked to original sources
PubMed2005

Blue cone monochromatism: a phenotype and genotype assessment with evidence of progressive loss of cone function in older individuals.

AIM: To perform a detailed clinical and psychophysical assessment of the members of three British families affected with blue cone monochromatism (BCM), and to determine the molecular basis of disease in these families. METHODS: Affected and unaffected members of three families with BCM were examined clinically and underwent electrophysiological and detailed psychophysical testing. Blood samples were taken for DNA extraction. The strategy for molecular analysis was to amplify the coding regions of the long wavelength-sensitive (L) and middle wavelength-sensitive (M) cone opsin genes and the upstream locus control region by polymerase chain reaction, and to examine these fragments for mutations by direct sequencing. RESULTS: We have confirmed the reported finding of protan-like D-15 arrangements of patients with BCM. In addition, we have demonstrated that the Mollon-Reffin (MR) Minimal test is a useful colour-discrimination test to aid in the diagnosis of BCM. Affected males were shown to fail the protan and deutan axes, but retained good discrimination on the tritan axis of the MR test, a compelling evidence for residual colour vision in BCM. This residual tritan discrimination was also readily detected with HRR plates. In two families, psychophysical testing demonstrated evidence for progression of disease. In two pedigrees, BCM could be linked to unequal crossovers within the opsin gene array that resulted in a single 5'-L/M-3' hybrid gene, with an inactivating Cys203Arg mutation. The causative mutations were not identified in the third family. CONCLUSIONS: The MR test is a useful method of detecting BCM across a wide range of age groups; residual tritan colour discrimination is clearly demonstrated and allows BCM to be distinguished from rod monochromatism. BCM is usually classified as a stationary cone dysfunction syndrome; however, two of our families show evidence of progression. This is the first report of progression associated with a genotype consisting of a single 5'-L/M-3' hybrid gene carrying an inactivating mutation. We have confirmed that the Cys203Arg inactivating mutation is a common sequence change in blue cone monochromats.

Adolescent↗
PubMed2006

The Mcp element mediates stable long-range chromosome-chromosome interactions in Drosophila.

Chromosome organization inside the nucleus is not random but rather is determined by a variety of factors, including interactions between chromosomes and nuclear components such as the nuclear envelope or nuclear matrix. Such interactions may be critical for proper nuclear organization, chromosome partitioning during cell division, and gene regulation. An important, but poorly documented subset, includes interactions between specific chromosomal regions. Interactions of this type are thought to be involved in long-range promoter regulation by distant enhancers or locus control regions and may underlie phenomena such as transvection. Here, we used an in vivo microscopy assay based on Lac Repressor/operator recognition to show that Mcp, a polycomb response element from the Drosophila bithorax complex, is able to mediate physical interaction between remote chromosomal regions. These interactions are tissue specific, can take place between multiple Mcp elements, and seem to be stable once established. We speculate that this ability to interact may be part of the mechanism through which Mcp mediates its regulatory function in the bithorax complex.

ATP-Binding Cassette Transporters↗
PubMed1994

Scaffold attachment regions stimulate HSP70.1 expression in mouse preimplantation embryos but not in differentiated tissues.

Eukaryotic interphase chromatin is thought to be organized into topologically discrete, independent domains acting as units upon which differential patterns of gene expression are established. Sequences which attach chromatin to in vitro preparations of a nucleoprotein matrix (scaffold attachment regions [SARs]) may act as domain boundaries, but their role remains poorly defined compared with those of other elements such as locus control regions. We have produced mice homozygous for a transgene which is transcribed as early as the activation of the embryonic genome at the two-cell stage and which is expressed ubiquitously in a number of differentiated tissues. Transgenic lines were generated in the presence or absence of flanking SAR sequences, creating an original model which enabled us to examine the effects of these elements at different developmental stages. In the preimplantation mouse embryo, flanking SARs stimulated transgene expression in a copy-dependent manner. In contrast, in the differentiated tissues of newborn and adult mice, no significant SAR-dependent increase in transgene expression was found, correlation with copy number was lost, and position effects were observed. These results suggest a limited capacity of SARs to act as insulating elements but are consistent with a proposed model of SAR-mediated chromatin opening and closing.

Aging↗
PubMed1995

Identification of two novel regulatory elements within the 5'-untranslated region of the human A gamma-globin gene.

Interaction between the stage selector element (SSE) in the proximal gamma-globin promoter and hypersensitivity site 2 in the locus control region partly mediates the competitive silencing of the beta-globin promoter in the fetal developmental stage. We have now demonstrated that a second SSE-like element in the 5'-untranslated region of the gamma-gene also contributes to this competitive silencing of the beta-gene. Utilizing transient transfection assays in the fetal erythroid cell line, K562, we have shown that the core enhancer of hypersensitivity site 2 can preferentially interact with the proximal gamma-promoter in the absence of the SSE, completely silencing a linked beta-promoter. Mutation of a 20-base pair sequence of the gamma-gene 5'-untranslated region (UTR) led to derepression of beta-promoter activity. A marked activation of gamma-promoter activity was also observed with this mutation, suggesting the presence of a repressor. Fine mutagenesis dissected these activities to different regions of the 5'-UTR. The stage selector activity was localized to a region centered on nucleotides +13 to +15. Electromobility shift assays utilizing this sequence demonstrated binding of a fetal and erythroid-specific protein. The repressor activity of the 5'-UTR was localized to tandem GATA-like sites, which appear to bind a complex of two proteins, one of which is the erythroid transcription factor GATA-1. These results indicate that the 5'-UTR of the gamma-gene contains sequences that may be important for its transcriptional and developmental regulation.

Base Sequence↗
PubMed2004

Response to hydroxyurea treatment in Iranian transfusion-dependent beta-thalassemia patients.

BACKGROUND AND OBJECTIVES: Hydroxyurea (HU) is known to increase gamma-globin chain expression in postnatal life. The efficacy of HU treatment in thalassemia patients is still unclear. The aim of this study was to monitor treatment of a large cohort of patients with beta-thalassemia major in order to establish the response to HU and the associated elements. DESIGN AND METHODS: HU therapy was started in 133 patients diagnosed with transfusion-dependent beta-thalassemia in 1999. The molecular background of the disease, the polymorphisms of the promoter region of the genes, the haplotype of the beta-globin gene cluster, the alpha-gene deletions and the HS2 polymorphism at the locus control region (LCR) of the beta-globin gene cluster were studied. RESULTS: We were able to classify three categories of response: a good response (61%) in patients who shifted from monthly blood transfusion dependency to a stable transfusion-free condition at an average Hb level of more than 10 gm/dL; a moderate response (23%) in patients who remained transfusion dependent but at longer intervals (6 months or more), and non response in patients who, after one year of treatment, remained at the same level of transfusion dependency. The correlations with the molecular defects were found to be secondary to the presence of the (C-->T) at -158 of the Ggamma gene (XmnI polymorphism). The T allele, in linkage to the haplotype I (+----) and to the internal beta-globin gene framework 2, was the most significant modulating factor involved. INTERPRETATION AND CONCLUSIONS: The good response to HU treatment that a significant number of southwest Iranian patients with beta-thalassemia patients had seems to correlate with particular haplotypes. This indicates that HU treatment is a sensible option for transfusion-dependent beta-thalassemia patients with a favorable molecular background.

Adolescent↗
PubMed1999

Conservation of sequence and structure flanking the mouse and human beta-globin loci: the beta-globin genes are embedded within an array of odorant receptor genes.

In mouse and human, the beta-globin genes reside in a linear array that is associated with a positive regulatory element located 5' to the genes known as the locus control region (LCR). The sequences of the mouse and human beta-globin LCRs are homologous, indicating conservation of an essential function in beta-globin gene regulation. We have sequenced regions flanking the beta-globin locus in both mouse and human and found that homology associated with the LCR is more extensive than previously known, making up a conserved block of approximately 40 kb. In addition, we have identified DNaseI-hypersensitive sites within the newly sequenced regions in both mouse and human, and these structural features also are conserved. Finally, we have found that both mouse and human beta-globin loci are embedded within an array of odorant receptor genes that are expressed in olfactory epithelium, and we also identify an olfactory receptor gene located 3' of the beta-globin locus in chicken. The data demonstrate an evolutionarily conserved genomic organization for the beta-globin locus and suggest a possible role for the beta-globin LCR in control of expression of these odorant receptor genes and/or the presence of mechanisms to separate regulatory signals in different tissues.

Animals↗
PubMed2006

Lineage-specific activators affect beta-globin locus chromatin in multipotent hematopoietic progenitors.

During development, the regulated expression of tissue-specific genes can be preceded by their potentiation, that is, by chromatin activation in progenitor cells. For example, the human beta-like globin genes are potentiated in a gene- and developmental-specific manner in hematopoietic progenitors. Developmental regulation of human beta-gene expression in erythroid cells is mostly determined by transcriptional activators; however, it is not clear how gene-specific potentiation is set in hematopoietic progenitors. Using human and transgenic multipotent hematopoietic progenitors, we demonstrate that human beta-globin locus activation is characterized by TBP, NF-E2, CBP and BRG1 recruitment at both the Locus Control Region and human beta-gene promoter. Our results further indicate that in hematopoietic progenitors, EKLF influences chromatin organization at the human beta-globin locus and is instrumental for human beta-gene potentiation. Thus, we show that lineage-specific transcriptional activators expressed at basal levels in progenitor cells can participate in gene potentiation.

Animals↗
PubMed1995

A promoter within intron 35 of the human C4A gene initiates abundant adrenal-specific transcription of a 1 kb RNA: location of a cryptic CYP21 promoter element?

Complement component C4 is encoded by two nearly identical genes, C4A and C4B, that encode a C4 precursor that is proteolytically cleaved into the alpha, beta and gamma subunits of the mature protein. C4 is expressed primarily in liver and to a much lesser extent in immune cells. We have identified a unique 1 kb RNA transcript, termed Z, that arises from a cryptic promoter lying in the intron between exons 35 and 36 of the C4 gene. Primer extension, RNase protection, and 5' RACE experiments locate the cap site in intron 35, 55 bases upstream from exon 36. Northern blotting and RNase protection assays show that expression of this 1 kb Z RNA transcript is confined to the adrenal gland. Z RNA contains the same open reading frame as C4 which predicts a protein of 131 amino acids, but antisera to C4 do not interact with epitopes on this protein when it is synthesized by cell-free translation, hence the presence or absence of a Z protein in vivo could not be determined. Transfection of Z promoter/reporter constructs into human adrenal NCI-H295 cells shows that most if not all of the sequences required for high-level adrenal expression lie within 235 bases upstream from the cap site, but that this region is inactive when transfected into COS-1, JEG-3 and Hep-G2 cells, suggesting it contains an adrenal-specific element. The 222 bases upstream from the cap site are 75% identical in the human C4A and mouse Slp genes, and contain a potential binding site for steroidogenic factor 1 (SF-1), an orphan zinc-finger nuclear receptor. We propose that this region, like a nearby region in the mouse genome, functions as an upstream element of the P450c21 promoter, and may be a component of an adrenal-specific locus-control region.

Adrenal Glands↗
PubMed1999

Development of viral vectors for gene therapy of beta-chain hemoglobinopathies: optimization of a gamma-globin gene expression cassette.

Progress toward gene therapy of beta-chain hemoglobinopathies has been limited in part by poor expression of globin genes in virus vectors. To derive an optimal expression cassette, we systematically analyzed the sequence requirements and relative strengths of the Agamma- and beta-globin promoters, the activities of various erythroid-specific enhancers, and the importance of flanking and intronic sequences. Expression was analyzed by RNase protection after stable plasmid transfection of the murine erythroleukemia cell line, MEL585. Promoter truncation studies showed that the Agamma-globin promoter could be deleted to -159 without affecting expression, while deleting the beta-globin promoter to -127 actually increased expression compared with longer fragments. Expression from the optimal beta-globin gene promoter was consistently higher than that from the optimal Agamma-globin promoter, regardless of the enhancer used. Enhancers tested included a 2.5-kb composite of the beta-globin locus control region (termed a muLCR), a combination of the HS2 and HS3 core elements of the LCR, and the HS-40 core element of the alpha-globin locus. All three enhancers increased expression from the beta-globin gene to roughly the same extent, while the HS-40 element was notably less effective with the Agamma-globin gene. However, the HS-40 element was able to efficiently enhance expression of a Agamma-globin gene linked to the beta-globin promoter. Inclusion of extended 3' sequences from either the beta-globin or the Agamma-globin genes had no significant effect on expression. A 714-bp internal deletion of Agamma-globin intron 2 unexpectedly increased expression more than twofold. With the combination of a -127 beta-globin promoter, an Agamma-globin gene with the internal deletion of intron 2, and a single copy of the HS-40 enhancer, gamma-globin expression averaged 166% of murine alpha-globin mRNA per copy in six pools and 105% in nine clones. When placed in a retrovirus vector, this cassette was also expressed at high levels in MEL585 cells (averaging 75% of murine alpha-globin mRNA per copy) without reducing virus titers. However, recombined provirus or aberrant splicing was observed in 5 of 12 clones, indicating a significant degree of genetic instability. Taken together, these data demonstrate the development of an optimal expression cassette for gamma-globin capable of efficient expression in a retrovirus vector and form the basis for further refinement of vectors containing this cassette.

Anemia, Sickle Cell↗
PubMed1993

Characterization of the DNase I hypersensitive site 3' of the human beta globin gene domain.

The members of the human beta globin gene family are flanked by strong DNase I hypersensitive sites. The collection of sites 5' to the epsilon globin gene is able to confer high levels of expression of linked globin genes, but a function has not been assigned to the site 3' to the beta globin gene (3'HS1). Our analysis of this DNase I super hypersensitive site shows that the region is composed of multiple DNase I sites. By examination of the DNA sequence, we have determined that the region is very A/T-rich and contains topoisomerase II recognition sequences, as well as several consensus binding motifs for GATA-1 and AP-1/NF-E2. Gel mobility shift assays indicate that the region can interact in vitro with GATA-1 and AP-1/NF-E2, and functional studies show that the region serves as a scaffold attachment region in both erythroid and nonerythroid cell lines. Whereas many of the physical features of 3'HS1 are shared by 5'HS2 (a component of the 5' locus control region), transient expression studies show that 3' HS1 does not share the erythroid-specific enhancer activity exhibited by 5'HS2.

Base Sequence↗
PubMed1998

HbS/beta(del)-thalassemia associated with high levels of hemoglobins A2 and F in a Turkish family.

Beta-thalassemia and sickle cell disease (SCD) are common disorders in Turkey. Compound heterozygosity for these two disorders (betaS/beta-thalassemia) is encountered frequently. In this report we present hematological and molecular data of two Turkish siblings with betaS/beta(del)-thalassemia caused by a 290 base pair (bp) deletion and associated with increased levels of hemoglobin A2 (HbA2) and hemoglobin F (HbF). Clinical analysis of the two patients showed a mild course of the disease. Haplotypic factors involved in increasing the levels of HbF were analyzed. The two patients showed no changes from the normal sequences at the XmnI site of Ggamma-globin promoter and the (AT)xTy microsatellite 5' to the beta-globin mRNA cap site. The removal of the region between positions -125 to +78 relative to the beta-globin gene mRNA cap site by the 290 bp deletion is thought to allow the beta-locus control region to interact with the promoters of the delta- and gamma-globin genes, leading to increased HbA2 and HbF levels.

Adult↗
PubMed2003

Identification and characterization of a DNase hypersensitive region of the human tyrosinase gene.

Mutations of the tyrosinase gene produce oculocutaneous albinism type 1 (OCA1). Most affected individuals are compound heterozygotes with different maternal and paternal mutations, but a substantial number of presumed tyrosinase alleles in these individuals have no identifiable mutation in the coding or proximal promoter region of the gene. This suggests that mutations in other regions of the gene, such as regulatory regions that are removed from the direct proximity of the coding sequence, may account for these currently unidentifiable mutations. The mouse tyrosinase gene has a distal enhancer or locus control region (LCR) that provides position-independent stimulation of gene expression, and a homologous regulatory region (HR) of the human gene could be the site of some of these mutations. We report a region 9 kb upstream of the human tyrosinase transcriptional start site that may be involved in regulation of this gene. Analysis of this region shows DNase I hypersensitivity in a cell lineage-specific pattern, a pattern indicative of regulatory regions of a gene. This region also has significant enhancer function when reporter vectors containing it are transfected into either human or mouse melanocyte cell lines, and elimination of specific sequences with homology to the mouse core enhancer in this region extinguishes the enhancer function. We believe that this region of homology contains sequences critical in the regulation of the human tyrosinase gene and is a candidate for the location of OCA1 mutations.

Albinism, Oculocutaneous↗
PubMed1999

Genomic sequence comparison of the human and mouse adenosine deaminase gene regions.

A challenge for mammalian genetics is the recognition of critical regulatory regions in primary gene sequence. One approach to this problem is to compare sequences from genes exhibiting highly conserved expression patterns in disparate organisms. Previous transgenic and transfection analyses defined conserved regulatory domains in the mouse and human adenosine deaminase (ADA) genes. We have thus attempted to identify regions with comparable similarity levels potentially indicative of critical ADA regulatory regions. On the basis of aligned regions of the mouse and human ADA gene, using a 24-bp window, we find that similarity overall (67.7%) and throughout the noncoding sequences (67.1%) is markedly lower than that of the coding regions (81%). This low overall similarity facilitated recognition of more highly conserved regions. In addition to the highly conserved exons, ten noncoding regions >100 bp in length displayed >70% sequence similarity. Most of these contained numerous 24-bp windows with much higher levels of similarity. A number of these regions, including the promoter and the thymic enhancer, were more similar than several exons. A third block, located near the thymic enhancer but just outside of a minimally defined locus control region, exhibited stronger similarity than the promoter or thymic enhancer. In contrast, only fragmentary similarity was exhibited in a region that harbors a strong duodenal enhancer in the human gene. These studies show that comparative sequence analysis can be a powerful tool for identifying conserved regulatory domains, but that some conserved sequences may not be detected by certain functional analyses as transgenic mice.

Adenosine Deaminase↗
PubMed2005

Regional abnormalities in retinal development are associated with local ocular hypopigmentation.

The retinal pigment epithelium (RPE) plays a key role in regulating retinal development. The critical enzyme in pigment production is tyrosinase. Transgenic mice with a tyrosinase construct where the locus control region was deleted (YRT4) display a variegated phenotype of tyrosinase expression. Their central retina is largely pigment free, whereas more peripheral regions are heavily pigmented. We have used this model to ask whether the influence of pigmented RPE over the retina during development is fundamentally governed by local interactions or is global. Our data show that YRT4 eyes have intermediate melanin content and relatively low tyrosinase activity compared with wild-type and albino animals. Rod counts are comparable to those in pigmented mice in peripheral regions but similar to those in albinos centrally. Anterograde labelling of retinal pathways demonstrates the presence of relatively normal ipsilateral chiasmatic projection in YRT4 mice, comparable with that in pigmented animals and consistent with the peripheral pigmented origin of this pathway. Examination of cellular proliferation levels during retinal development reveals that YRT4 mice display an extended period of mitosis, similar to that found in albinos. Hence, our results show that the regulatory influence of the RPE over the developing retina depends on localized interactions between these tissues.

Albinism, Ocular↗
PubMed2006

Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements.

Physical interactions between genetic elements located throughout the genome play important roles in gene regulation and can be identified with the Chromosome Conformation Capture (3C) methodology. 3C converts physical chromatin interactions into specific ligation products, which are quantified individually by PCR. Here we present a high-throughput 3C approach, 3C-Carbon Copy (5C), that employs microarrays or quantitative DNA sequencing using 454-technology as detection methods. We applied 5C to analyze a 400-kb region containing the human beta-globin locus and a 100-kb conserved gene desert region. We validated 5C by detection of several previously identified looping interactions in the beta-globin locus. We also identified a new looping interaction in K562 cells between the beta-globin Locus Control Region and the gamma-beta-globin intergenic region. Interestingly, this region has been implicated in the control of developmental globin gene switching. 5C should be widely applicable for large-scale mapping of cis- and trans- interaction networks of genomic elements and for the study of higher-order chromosome structure.

Base Sequence↗
PubMed2002

Isolated growth hormone deficiency and the GH-1 gene: update 2002.

This short review will focus on the mechanisms which are thought to be directly involved in GH expression and particularly on the monogenetic disorders which were shown to cause isolated growth hormone deficiency (IGHD) due to insufficient expression of GH. The overwhelming majority of genetic defects detected in isolated growth hormone deficiency (IGHD) are mutations of the coding region of the GH-1 gene which belongs to a five genes containing gene cluster located on 17q22-24. Depending on the type of the GH-1 gene mutation, the mode of inheritance is recessive or dominant. The promotor region of the GH-1 gene which encompasses the 300 bp of the 5' flanking region is highly polymorphic, but the functionally important cis-acting elements are conserved. This sequence is sufficient to control GH expression in cultured cells, but not in transgenic mice: the human GH locus control region, an enhancer region of the GH-1 gene located approximately 15-32 kB upstream of the GH-1 coding region was shown to direct pituitary-specific, high-level GH expression in vivo. Promotion of the GH expression needs the coordinate binding of pituitary-specific (i.e., POU1F1) and ubiquitous trans-acting factors to the cis-acting elements. The mutational analysis of trans-acting factors and cis-acting elements of the GH-1 gene has so far not established any defect outside the coding region as the genetic basis of IGHD except for POU1F1 mutations which cause multiple pituitary hormone deficiency including GHD. Several mutations of the GHRH-receptor gene were shown to result in severe IGHD. In the future, the discovery of new defects of the GH expression machinery will add to our understanding of how GH is sufficiently supplied to the organism and will hopefully simplify and improve the diagnostic approach in a subset of children with IGHD.

Human Growth Hormone↗
PubMed1994

Increased binding of Sp1 to the gamma-globin gene promoter upon site-specific cytosine methylation.

We have studied the effect of site-specific cytosine methylation on the binding of nuclear proteins to the gamma-globin promoter region from -71 to -34. This sequence was recently shown to contain a stage selector element responsible for increased transcription from the gamma compared to the beta promoter when both are linked to Locus Control Region enhancer sequences. We observed that Sp1 binding to this sequence is increased upon site-specific cytosine methylation, such that only methylation of the cytosine in the -50 CpG dinucleotide effects Sp1 binding. Methylation of the distal C of the Hpall site has no effect. The possible functional role of Sp1 as a repressor of gamma-globin synthesis is discussed.

Animals↗
PubMed1993

Homeodomain protein binding sites, inverted repeats, and nuclear matrix attachment regions along the human beta-globin gene complex.

beta-Globin genes in primates arose during evolution by duplication of an ancestral gene, and their order of arrangement along the DNA is related to their timing of expression during development. We believe that nuclear matrix anchorage sites (MARs) along the beta-globin gene complex considered to be mass binding sites for transcription protein factors, some of which are developmental stage specific and others ubiquitous, play a decisive role in cell memory by determining the developmental stage-specific expression of the genes. The AT-rich class of MARs appears to possess a significant number of ATTA and ATTTA motifs known to be mass binding sites for homeodomain proteins that determine body formation in development. MARs also appear to harbor origins of replication, to be enriched in inverted repeats (dyad symmetry motifs) and were proposed to include the DNase I hypersensitive sites of a particular gene determined at the chromatin level. This study is an attempt to finely identify MARs at the nucleotide level along the beta-globin gene complex. Searches of a contiguous stretch of about 73.3 kb of human sequences comprising and surrounding the epsilon, gamma G-, gamma A-, delta-, and beta-globin genes of the human beta-globin gene complex for homeotic protein binding sites as well as for inverted repeats has shown that these elements are clustered nonrandomly at particular sites within the beta-globin gene complex. These sites are presumed to be the AT-rich class of MARs of the beta-globin gene complex. The inverted repeats which are characteristic of origins of replication and some promoter/enhancer regions and the homeotic protein sites seem to include the DNase I hypersensitive sites of the gene complex. Indeed, dyad symmetry sequences are present close to the four DNase I HS sites in the locus control region (LCR) of the gene complex as well as in the 5' flanking regions and the large introns of the delta- and beta-globin genes. A search of the putative MAR regions of the gene complex suggests that, in addition to their enrichment in ATTA motifs, palindromes, and DNase I hypersensitive sites, these regions may comprise TG-rich motifs and potential Z-DNA as well as polypurine and polypyrimidine blocks. From the positions of palindromes and clusters of homeodomain protein sites along the complex we propose that an extended origin of replication able to initiate at several sites is present in the LCR and two others surrounding the delta- and beta-globin genes.(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗