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Biomedical subjects

R S Sparkes

Publications and source records attributed to R S Sparkes.

At least 19 recordsLinked to original sources
PubMed1992

Cloning and chromosomal mapping of a human immunodeficiency virus 1 "TATA" element modulatory factor.

A critical regulatory element in many promoters transcribed by RNA polymerase II is the "TATA" box, which is located 25-30 nucleotides upstream of the transcription initiation site. TFIID is a biochemically defined HeLa cell nuclear fraction containing a transcription factor activity that binds specifically to the TATA box and is critical in determining both basal and regulated promoter activity. Recently, the gene for a TATA-binding protein was cloned and found to bind to various TATA elements and to substitute for TFIID in stimulating basal gene expression in in vitro transcription systems. However, it is possible that additional cellular factors can bind to the TATA element and influence the level of gene expression. By using lambda gt11 expression cloning with oligonucleotides corresponding to the human immunodeficiency virus 1 TATA element, we report the identification of a cellular protein with a calculated molecular mass of 123 kDa that we designate TATA element modulatory factor (TMF). TMF binds to the human immunodeficiency virus 1 TATA element in gel-retardation assays and inhibits activation of the viral long terminal repeat by the TATA-binding protein in in vitro transcription assays. TMF contains leucine-zipper amino acid motifs and exhibits homology in its DNA binding domain with the phage-encoded DNA binding protein Ner. Chromosomal mapping localizes the TMF gene to human chromosome 3p12-p21, which is a site of frequent rearrangements in lung and renal carcinomas. Thus, TMF is a transcription factor that likely regulates the expression of both viral and cellular genes.

Amino Acid Sequence↗
PubMed1992

Startle disease, or hyperekplexia: response to clonazepam and assignment of the gene (STHE) to chromosome 5q by linkage analysis.

Familial startle disease (also known as hyperekplexia and congenital "stiff-man" syndrome) is an autosomal dominant disorder characterized by an exaggerated startle reaction of sudden, unexpected auditory or tactile stimuli; affected neonates also have severe and occasionally fatal hypertonia. We recently encountered a large, five-generation family with startle disease, and treated 16 patients (including 1 neonate) with clonazepam; all experienced dramatic and sustained improvement. We performed systematic linkage analysis in this family, and found tight linkage between the disease locus and a polymorphic genetic marker locus (colony-stimulating factor receptor, or CSF1R) that has been physically mapped to chromosome 5q33-q35. The maximum odds ratio favoring linkage over nonlinkage is greater than 10,000,000:1 (lod score, 7.10) at 3% recombination. Several genes encoding neurotransmitter receptor components have been physically mapped to the subtelomeric region of chromosome 5q, and are thus candidates for the startle disease gene. The availability of additional large pedigrees with startle disease should facilitate identification and characterization of the gene for this disorder.

Adult↗
PubMed1992

Localisation of the gene for Norrie disease to between DXS7 and DXS426 on Xp.

A highly informative microsatellite marker, DXS426, which maps proximal to DXS7 in the interval Xp11.4-Xp11.23, has been used to refine further the localisation of the gene for Norrie disease (NDP). The results from a multiply informative crossover localize the NDP gene proximal to DXS7. In conjunction with information from 2 NDP patients who have a deletion for DXS7 but not for DSX426, our data indicate that the NDP gene lies between DXS7 and DXS426 on proximal Xp.

Base Sequence↗
PubMed1992

Assignment of the beta-subunit of rod photoreceptor cGMP phosphodiesterase gene PDEB (homolog of the mouse rd gene) to human chromosome 4p16.

The gene encoding the beta-subunit of rod photoreceptor cGMP phosphodiesterase (gene symbol PDEB, homolog of the mouse rd gene) is mapped to human chromosome 4 using somatic cell hybrids and further localized to the chromosome band 4p16 using in situ hybridization. A mutation in the mouse gene underlies the recessive trait of retinal degeneration in the rd mouse. Thus, the human homolog is a candidate for lesions causing retinal degeneration.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1992

Mapping of the gene for the cardiac sarcolemmal Na(+)-Ca2+ exchanger to human chromosome 2p21-p23.

The cardiac sarcolemmal Na(+)-Ca2+ exchanger is the primary mechanism for extrusion of calcium from the cardiac myocyte and therefore is important in regulating cardiac contractility. As part of an effort to determine whether the exchanger is associated with any genetic disorders of the heart or blood pressure, we have assigned the exchanger gene (designated NCX1) to human chromosome 2p21-p23 by analysis of a panel of mouse-human somatic cell hybrids and by in situ hybridization.

Animals↗
PubMed1992

The L-isoaspartyl/D-aspartyl protein methyltransferase gene (PCMT1) maps to human chromosome 6q22.3-6q24 and the syntenic region of mouse chromosome 10.

We have mapped the genes for the human and mouse L-isoaspartyl/D-aspartyl protein carboxyl methyltransferase (EC 2.1.1.77) using cDNA probes. We determined that the human gene is present in chromosome 6 by Southern blot analysis of DNA from a panel of mouse-human somatic cell hybrids. In situ hybridization studies allowed us to confirm this identification and further localize the human gene (PCMT1) to the 6q22.3-6q24 region. By analyzing the presence of an EcoRI polymorphism in DNA from backcrosses of C57BL/6J and Mus spretus strains of mice, we localized the mouse gene (Pcmt-1) to chromosome 10, at a position 8.2 +/- 3.5 cM proximal to the Myb locus. This region of the mouse chromosome is homologous to the human 6q24 region.

Animals↗
PubMed1992

Cloning of the human cholesterol 7 alpha-hydroxylase gene (CYP7) and localization to chromosome 8q11-q12.

Cholesterol 7 alpha-hydroxylase (7 alpha-hydroxylase) is a microsomal cytochrome P450 that catalyzes the first step in bile acid synthesis. In this paper, we describe the cloning, characterization, and chromosomal mapping of the human 7 alpha-hydroxylase gene (CYP7). The gene spans 10 kb and contains six exons and five introns. The exon-intron boundaries are completely conserved between the human and rat genes. Sequencing of the 5' flanking region revealed consensus recognition sequences for a number of liver-specific transcription factors. The human CYP7 gene was mapped to chromosome 8q11-q12 using both mouse-human somatic cell hybrids and in situ chromosomal hybridization studies. A total of four single-stranded conformation-dependent DNA polymorphisms and an Alu sequence-related polymorphism were identified. Of the individuals analyzed, 80% were heterozygous for at least one of these five polymorphisms. The localization and characterization of the human 7 alpha-hydroxylase gene, as well as the identification of polymorphisms, provide the molecular tools necessary to investigate the role of this gene in disorders of cholesterol and bile acid metabolism.

Amino Acid Sequence↗
PubMed1992

Genetic marker associations with proliferative retinopathy in persons diagnosed with diabetes before 30 yr of age.

It has been suggested that HLA-DR4 is a marker of genetic predisposition to proliferative retinopathy. To investigate this relationship and potential associations between other polymorphic genes and proliferative retinopathy, a sample (n = 428) of participants in the population-based Wisconsin Epidemiologic Study of Diabetic Retinopathy was selected for typing for HLA-A, -B, -C, and -DR and a panel of other polymorphic genes. The presence of proliferative retinopathy was determined from grading of stereoscopic color fundus photographs taken at 2 examinations, 4 yr apart. In logistic regression models with repeated measures, persons with HLA-DR4 who were negative for DR3 were five times more likely to have proliferative retinopathy than those negative for both antigens after adjusting for other potential risk factors (Odds ratio = 5.43, 95% Confidence Interval (Cl) = 1.04, 28.30). HLA-C2, AK-2, and MNSs-S also were associated positively with proliferative retinopathy, and HLA-DR8 was associated inversely with this complication of diabetes in each case before adjusting for the number of comparisons. These data suggest that the genetically determined immunopathic mechanisms leading to diabetes, and in linkage disequilibrium with DR4, may independently contribute to the development of proliferative retinopathy.

Adolescent↗
PubMed1991

Monozygotic twins of discordant sex both with 45,X/46,X,idic(Y) mosaicism.

A female twin with short stature, unusual facial appearance, widely spaced nipples, and coarctation of the aorta was found to have a peripheral blood lymphocyte karyotype of 45,X(43%)/46,X,idic(Y)(p11). Her twin brother, also short with similar facial appearance, had the same mosaicism (40% 45,X). Cultured skin fibroblast studies showed discrepant karyotypes of 45,X (100%) in the girl and 45,X (78%)/46,X,idic(Y)(p11) in the boy. The mother and the father had normal chromosomes. Comparison of 27 biochemical markers yielded a likelihood of monozygosity of 0.9977. This report documents the occurrence of discordant phenotypic sex in monozygotic twins, involving gonadal dysgenesis with an abnormal dicentric Y, which presumably occurred de novo, followed by anaphase lag probably before the occurrence of twinning. Unequal distribution of the two resultant cell lines in various tissues of each twin could account for the development of the very different phenotypes, apparently normal boy and Ullrich-Turner girl.

Dermatoglyphics↗
PubMed1991

The cytogenetics of ataxia telangiectasia.

Ataxia-telangiectasia (AT) is a heterogeneous autosomal recessive disorder marked by cerebellar ataxia, oculocutaneous telangiectases, hypersensitivity to ionizing radiation, immunodeficiency, and cancer susceptibility. AT is also a spontaneous chromosomal breakage syndrome, notable for tissue-specific cytogenetic changes and telomeric fusions. Molecular characterization of rearrangements specific to T-lymphocytes suggests that a DNA repair/processing defect is potentially responsible for the diverse array of chromosomal abnormalities observed in a variety of AT cell types.

Ataxia Telangiectasia↗
PubMed1991

A U6 snRNA gene with an internal promoter is juxtaposed to an snRNP protein sequence within an intron of a human G protein gene.

A complex locus on human chromosome 1 brings together sequences homologous to a G protein and two components of the RNA processing machinery of eukaryotic cells. Specifically, the seventh intron of the human Gi3 alpha gene contains a fusion of a partial snRNP E protein pseudogene to a variant U6 snRNA gene. The novel U6 sequence contains nine point mutations and a one nucleotide deletion relative to the major U6 genes from humans. Unlike all other vertebrate U6 genes characterized to date, the variant U6 gene is efficiently transcribed by RNA polymerase III even in the absence of all natural flanking sequences. The union of elements from the signal transduction pathway and the RNA processing machinery suggests the possibility of functional interplay.

Amino Acid Sequence↗
PubMed1991

Confirmation of linkage between juvenile myoclonic epilepsy locus and the HLA region of chromosome 6.

Juvenile myoclonic epilepsy (JME) is a generalized, non-progressive epilepsy characterized by an adolescent onset of sudden, involuntary myoclonic jerks. Greenberg et al. (American Journal of Medical Genetics 31:185-192, 1988b; Cytogenetics and Cell Genetics 51:1008, 1989b) reported tight linkage of a JME locus to the HLA region of chromosome 6p. We confirm this linkage assignment, although at a larger recombination fraction than previously reported. Twenty-three, mostly nuclear, families were ascertained through a JME proband. The affected status of relatives of the probands was assigned by 4 different clinical criteria, and separate analyses were done assuming an autosomal dominant model with 90% penetrance and an autosomal recessive model with full penetrance. A linear age-of-onset correction with maximum penetrance at age 20 years was incorporated into the analyses. The maximum lod score obtained was 3.11 at (-)m = 0.001, (-)f = 0.20, assuming autosomal dominant inheritance and using the second definition of the disease phenotype. There was strong support for linkage using the other phenotype definitions and the autosomal dominant model, although the lod scores did not exceed 3.0. There was also support for linkage of a JME locus to this region under the autosomal recessive model, although the results varied depending upon the definition of the disease phenotype. There was no significant evidence for linkage heterogeneity.

Chromosome Mapping↗
PubMed1991

Hybrid leukemia and the 5q-abnormality.

Most cases of acute leukemia with deletions of chromosome 5q (5q-) are acute myelogenous leukemia. 5q- in acute lymphoid leukemia is rare. We studied a case of acute leukemia with 5q- using morphologic, cytochemical, immune and molecular techniques. Morphologic and cytochemical techniques were consistent with ALL (FAB L-2, PAS+, MPO-, ASD-). TdT was present. Immune studies suggested a T-cell phenotype (CD5+, CD7+); however, there was no rearrangement of the T beta-cell receptor gene. Surprisingly, the leukemia cells also expressed the CD13 myeloid antigen. Dual staining analysis showed co-expression of lymphoid and myeloid antigens on most cells. Based on these data and a review of previous reports we suggest that acute leukemia associated with the 5q- abnormality can occur in an immature stem cell resulting in a hybrid leukemia.

Adult↗
PubMed1991

Where does transformation occur in acute leukemia?

We studied 43 consecutive cases of acute leukemia for evidence of hybrid leukemia including biphenotypic or bilineal involvement. Twenty-two were initially diagnosed as acute lymphoblastic leukemia (ALL) and 21 as acute myelogenous leukemia (AML). Techniques included morphology, cytochemistry, immune phenotyping and cytogenetics. Thirty-one cases seemed restricted to one lineage. Twelve cases showed involvement of both lymphoid and myeloid cells. Dual staining immune phenotyping showed coexpression of diverse lineage markers. These data indicate a considerable proportion of unselected cases of acute leukemia are hybrid leukemias. These data are consistent with the notion that transformation frequently occurs in a stem or progenitor cell.

Acute Disease↗
PubMed1991

Assignment of the gene for cyclic AMP-response element binding protein 2 (CREB2) to human chromosome 2q24.1-q32.

The regulatory element TGACGTCA is found upstream of a number of viral and cellular genes. This element has been demonstrated to mediate cyclic AMP induction of cellular genes and activation of viral genes. A group of closely related cellular genes known as cyclic AMP-response element binding proteins (CREB) or activating transcription factor (ATF) have been found to bind to this motif and mediate activation by cyclic AMP and the adenovirus E1A protein. One of these genes, CREB1, was previously mapped to human chromosome 2q32.3-q34. Southern blot analysis of genomic DNA from a panel of mouse-human somatic cell hybrids indicated that the CREB2 gene, another member of this family, also resides on human chromosome 2. In situ hybridization further regionalized this gene to 2q24.1-q32. Thus, the genes for CREB1 and CREB2 that have only limited DNA sequence homology map to a similar region of the long arm of chromosome 2, though whether they are part of a gene cluster is unclear.

Activating Transcription Factor 2↗
PubMed1991

Assignment of human pancreatic lipase gene (PNLIP) to chromosome 10q24-q26.

Human pancreatic lipase (EC 3.1.1.3) is a 56-kDa protein secreted by the acinar pancreas and is essential for the hydrolysis and absorption of long-chain triglyceride fatty acids in the intestine. In vivo, the 12-kDa protein cofactor, colipase, is required to anchor lipase to the surface of lipid micelles, counteracting the destabilizing influence of bile salts. Southern blot analysis, using a pancreatic lipase cDNA to probe DNA from mouse-human somatic cell hybrids, indicated that the pancreatic lipase gene (PNLIP) resides on human chromosome 10. In situ hybridization to human metaphase chromosomes confirmed the cell hybrid results and further localized the gene to the 10q24-qter region with the strongest peak at q26.1.

Blotting, Southern↗