Biomedical subjects
Publications and source records attributed to R S Sparkes.
Three new families are reported for standard gene linkage markers and classical peripheral neurofibromatosis (Von Reckling-hausen disease). Additional data are summarised for the exclusion map. One family gives slight evidence of close linkage with the Gc locus on chromosome 4, raising again the question of possible genetic heterogeneity in NF.
We have identified and characterized two over-lapping bovine cDNA clones corresponding to the bovine crystallin beta Bp. The longer of the two clones, which contains the entire coding and 3' untranslated region as well as 54 nucleotides of the 5' untranslated sequence was used to identify and map an orthologous human gene, Hu beta B2, to chromosome 22, q11.2-q12.2. As one other human beta-crystallin, Hu beta A3/A1, has been mapped to chromosome 17, our results indicate that, unlike the tightly linked gamma-crystallins, the human beta-crystallins are not syntenic within the genome.
We have tested thirty-two phenotypic blood markers on sixteen families with with ataxia-telangiectasia (AT) in an attempt to identify the chromosomal location of the AT gene(s). Although at least five complementation groups have been defined, it is not known whether the corresponding AT genes are clustered or dispersed in the genome. Both clustered and dispersed genetic models were considered in linkage analyses. No significant linkages were found. The data exclude approximately 7 per cent of the autosomal genome for a 'clustered' model and 2 per cent of the autosomal genome for a 'dispersed' model. Several genomic areas were identified which warrant further study.
Gyrate atrophy is a hereditary chorioretinal degeneration associated with a deficiency of ornithine aminotransferase (OAT). By means of a complementary DNA clone encoding human OAT, the OAT gene sequences were mapped by somatic cell hybrids and in situ hybridization to human chromosome regions 10q26 and Xp11.2. A review of 80 biochemically confirmed cases of gyrate atrophy confirmed the autosomal recessive inheritance of this disease and supported the presence of a functional OAT gene on chromosome 10. Interestingly, the X chromosome OAT gene sequences (Xp11.2) map to the same region as L1.28 (Xp11.0-p11.3), a marker closely linked to X-linked recessive retinitis pigmentosa.
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase was purified to homogeneity from rat liver cytoplasm. The active enzyme is a dimer composed of identical subunits of Mr = 53,000. The amino acid composition and the NH2-terminal sequence are presented. Partial cDNA clones for the enzyme were isolated by screening of a rat liver lambda gt11 expression library with antibodies raised against the purified protein. The identity of the clones was confirmed by hybrid selection and translation. When rats were fed diets supplemented with cholesterol, cholestyramine, or cholestyramine plus mevinolin, the hepatic protein mass of cytoplasmic synthase, as determined by immunoblotting, was 25, 160, and 1100%, respectively, of the mass observed in rats fed normal chow. Comparable changes in enzyme activity were observed. Approximately 9-fold increases in both HMG-CoA synthase mRNA mass and synthase mRNA activity were observed when control diets were supplemented with cholestyramine and mevinolin. When rats were fed these two drugs and then given mevalonolactone by stomach intubation, there was a 5-fold decrease of synthase mRNA within 3 h. These results indicate that cytoplasmic synthase regulation occurs primarily at the level of mRNA. This regulation is rapid and coordinate with that observed for HMG-CoA reductase. The chromosomal localization of human HMG-CoA synthase was determined by examining a panel of human-mouse somatic cell hybrids with the rat cDNA probe. Interestingly, the synthase gene resides on human chromosome 5, which has previously been shown to contain the gene for HMG-CoA reductase. Regional mapping, performed by examination of a series of chromosome 5 deletion mutants and by in situ hybridization to human chromosomes indicates that the two genes are not tightly clustered.
Retinoblastoma is a childhood cancer, predisposition to which is inherited as an autosomal dominant trait. We used restriction-fragment-length and isozymic alleles of loci on chromosome 13 in five families predisposed to retinoblastoma, to provide identification before illness of persons likely to have tumors. The likelihood of disease was predicted in two cases, and freedom from disease in three. The calculated predictive accuracy was greater than 94 percent in cases with informative loci flanking the retinoblastoma (RB1) locus, and our prediction has been fulfilled in each such instance. A case that was informative at several loci indicated the occurrence of meiotic recombination, and accurate prediction was based on data obtained with DNA markers and isozymic forms of esterase D. The calculated predictive accuracy in another case, which was informative only for loci distal to the retinoblastoma locus, was about 70 percent. This patient was expected to acquire the disease but had not done so at the age of one year, illustrating the need for more markers that are also more informative and genetically closer to the retinoblastoma locus. These studies provide the basis for prenatal and postnatal prediction of susceptibility to inherited cancer using arbitrary recombinant DNA markers. Such predictions should make genetic counseling for familial retinoblastoma more accurate and lead to earlier tumor detection and more effective therapy.
Clinical studies and genetic linkage analysis in 64 members of a family with autosomal dominant congenital cataracts demonstrated intrafamilial variable expressivity and asymmetry between the two eyes. On the basis of 26 polymorphic phenotypic gene markers, linkage was excluded with the Duffy blood group (located on chromosome 1), haptoglobin (chromosome 16), and others. These data supported genetic heterogeneity of congenital cataracts as previous linkage assignments have included the pulverulent or Coppock cataract to chromosome 1 with Duffy and a posterior polar cataract to chromosome 16 with haptoglobin.
In an earlier paper, positive but nonsignificant lod scores were found in pair-wise linkage tests between multiple endocrine neoplasia type 2A (MEN-2A) and both the haptoglobin (HP) locus on chromosome 16 and group-specific component (GC) locus on chromosome 4. Recently discovered restriction fragment length polymorphisms for HP and for metallothionein 2 processed pseudogene 1 (MT2P1) near GC have made it possible to carry out a more powerful set of linkage tests with MEN-2A. This paper reports the results of such linkage analyses employing both pair-wise and multipoint tests. Close linkage of HP on chromosome 16 and MEN-2A is excluded. Linkage of MEN-2A on chromosome 4 with GC is excluded on the MT2P1 side of GC in a 7-centimorgan interval around MT2P1.
The gene map assignment of a human beta-crystallin gene to 17cen-q23 has been made using a bovine probe in the study of human-mouse and human-Chinese hamster somatic cell hybrids containing parts of human chromosome 17.
We have used hamster cDNA probes for 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (HMGCR) to determine the chromosomal location of the human gene for HMG CoA reductase. Southern blot analysis of genomic DNA from 16 independent mouse-human somatic cell hybrids showed that the human gene for HMG CoA reductase resides on chromosome 5. Analysis of Chinese hamster-human somatic cell hybrids selectively retaining human 5 or a portion of it showed that the gene locus for HMG CoA reductase can be assigned to the q13----q23 region of chromosome 5.
Apolipoprotein B (apoB) is the major protein component of low-density and very-low-density lipoproteins. We have recently isolated nonoverlapping cDNA clones for apoB and confirmed their identity by sequence comparisons. We now report the mapping of the human apoB gene (APOB) to the p23-p24 region of chromosome 2 by examination of human-mouse somatic cell hybrids and by in situ hybridization to human chromosomes. Thus, APOB is unlinked to members of the dispersed gene family encoding other apolipoprotein species or to the gene encoding the low-density lipoprotein receptor. Hybridization analysis with genomic DNA and liver and intestinal mRNA suggests that APOB encodes both the high-molecular-weight form of apoB (apoB100) incorporated into very-low-density lipoproteins in liver and the lower-molecular-weight form (apoB48) incorporated into chylomicrons in intestine. Restriction fragment length polymorphisms of APOB have been identified and should prove useful in examining the possibility that genetic variations of APOB are involved in dyslipoproteinemias and atherosclerosis.
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We report the regional mapping of human chromosome 19 genes for three apolipoproteins and a lipoprotein receptor as well as genes for three other markers. The regional mapping was made possible by the use of a reciprocal whole-arm translocation between the long arm of chromosome 19 and the short arm of chromosome 1. Examination of three separate somatic cell hybrids containing the long arm but not the short arm of chromosome 19 indicated that the genes for apolipoproteins CI, CII, and E (APOC1, APOC2, and APOE, respectively) and glucose-6-phosphate isomerase (GPI) reside on the long arm, whereas genes for the low density lipoprotein receptor (LDLR), complement component 3 (C3), and peptidase D (PEPD) reside on the short arm. When taken together with previous studies, our results suggest the following physical gene map: pter-LDLR-C3-p13.2-PEPD-centromere-(APOE, APOC1, APOC2, GPI)-qter. In addition, we have isolated a single lambda phage carrying both APOC1 and part of APOE. These genes are tandemly oriented and are separated by about 6 kilobases of genomic DNA. Since previous family studies indicate tight linkage of APOE and APOC2, the apolipoprotein genes APOC1, APOC2, and APOE form a tight complex on the long arm of chromosome 19, suggesting the possibility of coordinate regulation.
Purified preparations of scrapie prions contain one major macromolecule, designated prion protein (PrP). Genes encoding PrP are found in normal animals and humans but not within the infectious particles. The PrP gene was assigned to human chromosome 20 and the corresponding mouse chromosome 2 using somatic cell hybrids. In situ hybridization studies mapped the human PrP gene to band 20p12----pter. Our results should lead to studies of genetic loci syntenic with the PrP gene, which may play a role in the pathogenesis of prion diseases or other degenerative neurologic disorders.
Congenital heart disease occurred in 62% of the reported cases of supernumerary der(22) syndrome. These were most commonly acyanotic lesions such as atrial septal defect, ventricular septal defect or patent ductus arteriosus. Heart disease did not, however, appear to be a major determinant of survival.
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Analysis of immunoglobulin gene rearrangements in 16 B-cell lineages clonally propagated from two mononucleosis patients supported the notion that mononucleosis is a polyclonal B-lymphoproliferative disorder. Three of seven cell clones from a patient with a fatal B lymphoma revealed the same pattern of immunoglobulin gene rearrangement, indicating that this patient's disease was oligoclonal. The three similar clones were propagated from two sites (blood and spleen), indicating that they represent a metastatic cell lineage which arose during the patient's fatal B lymphoproliferation.
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