Search PubMed⌕ Search

Biomedical subjects

E Beutler

Publications and source records attributed to E Beutler.

At least 73 records · Page 4Linked to original sources
PubMed1998

The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms.

Nramp2 is a gene encoding a transmembrane protein that is important in metal transport, in particular iron. Mutations in nramp2 have been shown to be associated with microcytic anemia in mk/mk mice and defective iron transport in Belgrade rats. Nramp2 contains a classical iron responsive element in the 3' untranslated region that confers iron dependent mRNA stabilization. In this report, we describe a splice variant form of human nramp2 that has the carboxyl terminal 18 amino acids substituted with 25 novel amino acids and has a new 3' untranslated region lacking a classical iron-responsive element. This splice form of nramp2, nramp2 non-IRE, was found to be derived from splicing of an additional exon into the terminal coding exon. The nramp2 gene is comprised of 17 exons and spans more than 36 kb. It contains an additional 5' exon and intron (exon and intron 1) and an additional 3' exon (exon 17) and intron (intron 16) as compared to nramp1, a homologous gene. The additional exons and introns account for much of the difference in length between nramp2 (> 36 kb) and nramp1 (12 kb). The exon-intron borders of nramp2 exons 3-15 are homologous to nramp1 exons 2-14. The nramp2 5' regulatory region contains two CCAAT boxes but lacks a TATA box. The 5' regulatory region of nramp2 also contains five potential metal response elements (MRE's) that are similar to the MRE's found in the metallothionein-IIA gene, three potential SP1 binding sites and a single gamma-interferon regulatory element. Five single nucleotide mutations or polymorphisms were identified within the nramp2 gene. One of these, 1303C-->A, occurs in the coding region of nramp2 and results in an amino acid change from leucine to isolecine. A polymorphism, 1254T/C, also occurs in the coding region of nramp2 but does not cause an amino acid change. The other 3 polymorphisms are within introns (IVS2 + 11A/G, IVS4 + 44C/A, and IVS6 + 538G/Gdel). In addition, a polymorphic microsatellite TATATCTATATATC (TA)6-7 (CA)10-11 CCCCCTATA (TATC)3 (TCTG)5 TCCG (TCTA)6 was identified in intron 3. Analysis of cDNA derived by direct amplification of reversed transcribed RNA or cDNA clones isolated from a library provide evidence of skipping of exons 10 and 12 of nramp2. Deletion of either of these exons would result in a sequence that remains in frame yet would generate a protein that would lack transmembrane spanning region 7 or 8 respectively. The deletion of a single transmembrane domain would have severe topological consequences. The coding region of the nramp2 gene of hemochromatosis patients with or without mutations in the hemochromatosis gene, HFE, were examined and found to be normal. One hemochromatosis patient, with a normal HFE genotype, was heterozygous for the 1303C-->A mutation. Furthermore, in an examination of hemochromatosis patients with mutant HFE and normal HFE genes, we did not observe a linkage disequilibrium of either group with a particular nramp2 haplotype. These data suggest that mutations in nramp2 are not commonly associated with hemochromatosis.

Amino Acid Sequence↗
PubMed1998

Six new Gaucher disease mutations.

Six previously undescribed mutations were identified in 6 unrelated Gaucher disease patients: 437C-->T (107Ser-->Leu), 593C-->T (159Pro-->Leu), 604C-->T (163Arg-->Stop), 1138G-->A (341Ala-->Thr), 1214G-->A (366Ser-->Asn), 1294T-->A (393Trp-->Arg). Five patients were compound heterozygotes and 1 patient was a 593T/593T homozygote. Four patients had type I Gaucher disease with mild clinical phenotypes. Two other patients manifested central nervous system involvement (type II and type III).

Base Sequence↗
PubMed1998

Structure and linkage relationships of the region containing the human L-type pyruvate kinase (PKLR) and glucocerebrosidase (GBA) genes.

Both the L-type pyruvate kinase gene (PKLR) and glucocerebrosidase (GBA) gene are on band q21 of chromosome 1 in humans. Two overlapping P1 bacteriophage clones containing PKLR and GBA were identified and mapped, defining the locations of these two genes as well as those of the GBA pseudogene (psi GBA) metaxin (MTX), the MTX pseudogene (psi MTX), and thrombospondin 3 (THBS3). The distance between the 5' ends of GBA and PKLR was determined to be 71 kb. The direction of transcription PKLR gene was convergent to that of the GBA gene. All 195 Gaucher disease patients homozygous for the 1226G mutation, representing 390 chromosomes with the 1226G mutation, had a PvuII -/- GBA haplotype and a C/C at nt 1705 of the PKLR gene (-/- haplotype). All 56 Gaucher disease patients who were 1226G/84GG compound heterozygotes manifested a -/+ GBA haplotype and 55 of 56 patients were -/+ at PKLR nt 1705. Only 1 patient with 1226G/84GG genotype showed a crossover with the PKLR polymorphism, with a -/- haplotype at nt 1705. Similarly, 9 patients deficient in pyruvate kinase with the PKLR 1529A/1529A genotype were all found to have the same -/- GBA haplotype.

Chromosome Mapping↗
PubMed1997

Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia.

Severe jaundice leading to kernicterus or death in the newborn is the most devastating consequence of glucose-6-phosphate dehydrogenase (EC 1.1.1.49; G-6-PD) deficiency. We asked whether the TA repeat promoter polymorphism in the gene for uridinediphosphoglucuronate glucuronosyltransferase 1 (EC 2.4.1.17; UDPGT1), associated with benign jaundice in adults (Gilbert syndrome), increases the incidence of neonatal hyperbilirubinemia in G-6-PD deficiency. DNA from term neonates was analyzed for UDPGT1 polymorphism (normal homozygotes, heterozygotes, variant homozygotes), and for G-6-PD Mediterranean deficiency. The variant UDPGT1 promoter allele frequency was similar in G-6-PD-deficient and normal neonates. Thirty (22.9%) G-6-PD deficient neonates developed serum total bilirubin >/= 257 micromol/liter, vs. 22 (9.2%) normals (P = 0.0005). Of those with the normal homozygous UDPGT1 genotype, the incidence of hyperbilirubinemia was similar in G-6-PD-deficients and controls (9.7% and 9.9%). In contrast, in the G-6-PD-deficient neonates, those with the heterozygous or homozygous variant UDPGT1 genotype had a higher incidence of hyperbilirubinemia than corresponding controls (heterozygotes: 31.6% vs. 6.7%, P < 0.0001; variant homozygotes: 50% vs. 14.7%, P = 0.02). Among G-6-PD-deficient infants the incidence of hyperbilirubinemia was greater in those with the heterozygous (31.6%, P = 0.006) or variant homozygous (50%, P = 0.003) UDPGT1 genotype than in normal homozygotes. In contrast, among those normal for G-6-PD, the UDPGT1 polymorphism had no significant effect (heterozygotes: 6.7%; variant homozygotes: 14.7%). Thus, neither G-6-PD deficiency nor the variant UDPGT1 promoter, alone, increased the incidence of hyperbilirubinemia, but both in combination did. This gene interaction may serve as a paradigm of the interaction of benign genetic polymorphisms in the causation of disease.

Cohort Studies↗
PubMed1997

Three genes encoding zinc finger proteins on human chromosome 6p21.3: members of a new subclass of the Kruppel gene family containing the conserved SCAN box domain.

Five genes encoding zinc finger proteins of the Cys2His2 (or Krüppel) family were identified by direct cDNA hybridization to YACs 753H12 and 638D7, which encompass a region of human chromosome 6p21.3 extending from just centromeric of the microsatellite marker D6S306 to telomeric of D6S1260. The genes span a distance of approximately 1750 kb. The complete cDNA sequence, genomic structure, and tissue distribution of three of the zinc finger proteins, LD65/ZNF165, ZNF192 (previously called LD5-1), and ZNF193, are described. The three zinc finger proteins do not contain either Krüppel-associated box (KRAB) A or KRAB B domain, present in about one-third of all Krüppel-type zinc finger proteins (E. J. Bellefroid et al., 1991, Proc. Natl. Acad. Sci. USA 88: 3608-3612). The three zinc finger proteins do contain the conserved SCAN box domain (A. J. Williams et al., 1995, J. Biol. Chem. 270: 22143-22152). SCAN boxes are found in eight other genes in the GenBank database, five of which are also in the Kruppel family of zinc finger proteins lacking KRAB A and B domains and thereby define a new subclass of zinc finger proteins. In addition, three polymorphisms were identified in ZNF192, one of the zinc finger proteins. One of the three polymorphisms, Pro163Leu, is the second proline in a proline cluster (PEPP) in a region separating the SCAN box from the zinc finger motifs.

Amino Acid Sequence↗
PubMed1997

Molecular genetics of glucose-6-phosphate dehydrogenase deficiency in Mexico.

Several studies carried out between 1965 and 1985 showed that G-6-PD deficiency in Mexico is heterogeneous at the biochemical level and that the G-6-PD A- phenotype is relatively common. We have now investigated the molecular basis of G-6-PD deficiency in Mexico. Up-to-date 60 chromosomes with G6PD mutations have been studied, 16 in previous studies and 44 in the present work. Molecular analysis of DNA from G-6-PD deficient Mexican mestizos and their relatives show that G-6-PD A- genotypes are relatively common but also that in Mexico G-6-PD deficiency is heterogeneous at the DNA level. Thus, five different genotypes have been observed: G-6-PD A-(202A/376G) (41 chromosomes), G-6-PD A-(376G/968C) (14 chromosomes), G-6-PD Seattle844C (3 chromosomes), G-6-PD "Mexico City"680A (1 chromosome) and G-6-PD Guadalajara1159T (1 chromosome). The G-6-PD A-(202A/376G), G-6-PD A-(376G/968C) and G-6-PD Seattle844C mutations in Mexico are on the same Pvu II/ Pst I/ 1311 / Nla III haplotypes as found in individuals from Africa, Spain and the Canary Islands. Consequently, these mutations were probably imported to Mexico through African slaves and/or the Spanish immigrants during and after the colonization.

Adult↗
PubMed1997

HLA-H mutations in the Ashkenazi Jewish population.

Hereditary hemochromatosis is a common disorder in people of European origin. The HLA-H gene has been found to have two mutations that apparently cause hemochromatosis. The principal mutation, 845G-->A (C282Y), is believed to have arisen relatively recently in the Celtic population. To determine the incidence of this mutation and the other hemochromatosis-associated mutation, 187C-->G (H63D), among Ashkenazi Jews, a people who are believed to have arrived in Europe in about the 8th Century A.D., we have examined the DNA from 381 unrelated Jewish subjects and 206 non-Jewish white controls. The gene frequency for the 845G-->A mutation among Jewish subjects was only 0.013 compared with a frequency of 0.070 among controls, a difference that is significant at the 0.00001 level. The phenotypically milder nt 187C-->G mutation had a frequency of 0.155 in the non-Jewish population and 0.097 in the Jewish population, a difference that was also statistically significant at the <0.01 level.

Genotype↗
PubMed1997

Commentary

Explore the source record for details and available documents.

Journal Article↗
PubMed1997

New diallelic markers in the HLA region of chromosome 6.

Diallelic polymorphisms have been identified in the HLA-H gene and the ZNF192 gene located about 2 megabases centromeric to HLA-H. The three polymorphic sites in HLA-H together with the two hemochromatosis mutations in this gene give rise to 8 different haplotypes. The three polymorphic sites in ZNF192 give rise to 4 different haplotypes. The haplotypes in HLA-H are in complete linkage disequilibrium with the two common mutations in that gene, 845A (C282Y) and 187G (H63D). The 845A mutation is in weak linkage disequilibrium with the ZNF192 polymorphisms and the 187G mutation appears to be in equilibrium with this polymorphism. The 187G mutation therefore appears to be the older of the two HLA-H mutations.

Alleles↗