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Biomedical subjects

E Beutler

Publications and source records attributed to E Beutler.

At least 199 records · Page 11Linked to original sources
PubMed1992

The origin of glucose-6-phosphate-dehydrogenase (G6PD) polymorphisms in African-Americans.

DNA samples from 54 male Afro-Americans were examined for glucose-6-phosphate dehydrogenase (G6PD) genotypes G6PD A(+)376G, G6PD A(-)202A/376G, and G6PD B and for polymorphisms in intron 5 (PvuII), at nucleotide 1311, and at nucleotide 1116 (PstI). In the G6PD B subjects, the nucleotide 1311 mutation and the PstI site appeared to be in linkage equilibrium. No PvuII+ G6PD men were encountered. The G6PD A(+) mutation was in disequilibrium with respect to both the nucleotide 1311 mutation and the PstI site. The G6PD A- nucleotide 202 mutation was in disequilibrium with all three polymorphic sites. No conclusion could be drawn with respect to the PvuII site, except that it preceded the nucleotide 202 (A-) mutation. We conclude from these and our previous studies that G6PD B is the most ancient genotype. The nucleotide 1311 mutation, with its worldwide distribution, probably occurred next. The PstI mutation, limited to Africans, probably arose next and is more ancient than the A(+) mutation, which occurred in a gene without either the PstI or the 1311 mutation. G6PD A-202A/376G is the most recent of these mutations and is still in linkage disequilibrium with all of the sites. Presumably it occurred in an individual with both the A(+) and PvuII mutations.

Black People↗
PubMed1991

Identification of the second common Jewish Gaucher disease mutation makes possible population-based screening for the heterozygous state.

Gaucher disease is an autosomal recessive glycolipid storage disease characterized by a deficiency of glucocerebrosidase. The disease is most common in persons of Ashkenazi Jewish ancestry and the most common mutation, accounting for about 75% of the mutant alleles in this population, is known to be an A----G substitution at cDNA nucleotide (nt) 1226. Screening for this disease has not been possible because nearly 25% of the mutant alleles had not been identified, but linkage analysis led to the suggestion that most of these could be accounted for by a single mutation. We now report the discovery of this mutation. The insertion of a single nucleotide, a second guanine at cDNA nt 84 (the 84GG mutation), has been detected in the 5' coding region of the glucocerebrosidase gene. The amount of mRNA produced is shown to be normal but since the frameshift produced early termination, no translation product is seen. This finding is consistent with the virtual absence of antigen found in patients carrying this mutation. The 84GG mutation accounts for most of the previously unidentified Gaucher disease mutations in Jewish patients. The common Jewish mutation at nt 1226, the 84GG mutation, and the less-common mutation at nt 1448 accounted for 95% of all of the Gaucher disease-producing alleles in 71 Jewish patients. This now makes it possible to screen for heterozygotes on a DNA level with a relatively low risk of missing couples at risk for producing infants with Gaucher disease.

Age Factors↗
PubMed1991

Gaucher's disease.

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Gaucher Disease↗
PubMed1991

Enzyme replacement therapy for Gaucher disease.

Four patients with moderately severe type I Gaucher disease were treated with commercially available mannose terminated glucocerebrosidase (Ceredase; Genzyme, Boston, MA) for up to 13 months. The enzyme was administered at the rate of three to four times weekly at one fourth the total recommended dosage, greatly decreasing the cost. Marked regression of hepatomegaly and improvement in liver function tests, peripheral blood counts, and serum angiotensin-converting enzyme levels were documented. The two patients with pulmonary involvement manifested improvement in pulmonary function tests. Skeletal disease remained unchanged.

Adult↗
PubMed1991

DNA sequence abnormalities of human glucose-6-phosphate dehydrogenase variants.

Over 400 supposedly biochemically and genetically distinct variants of glucose-6-phosphate dehydrogenase (G6PD) have been described in the past. In order to investigate these variants at the DNA sequence level we have now determined the relevant sequences of introns of G6PD and describe a method which allows us to rapidly determine the sequence of the entire coding region of G6PD. This technique was applied to six variants that cause G6PD deficiency to be functionally so severe as to result in nonspherocytic hemolytic anemia. Although the patients were all unrelated, G6PD Marion, Gastonia, and Minnesota each had identical mutations, a G----T at nucleotide (nt) 637 in exon 6 leading to a Val----Leu substitution at amino acid 213. The mutations of Nashville and Anaheim were identical to each other, viz. G----A at nt 1178 in exon 10 producing a Arg----His substitution at amino acid 393. G6PD Loma Linda had a C----A substitution at nt 1089 in exon 10, producing a Asn----Lys change at amino acid 363. The results confirm our earlier results suggesting that the NADP-binding site is in a small region of exon 10 and suggest the possibility that this area is also concerned with the binding of glucose-6-P.

Anemia, Hemolytic, Congenital Nonspherocytic↗
PubMed1991

The loss of enzyme activity from erythroid cells during maturation.

Erythrocyte enzyme activities in patients with reticulocytosis or transient erythroblastopenia show that loss of age-dependent enzyme activity is not a simple exponential process occurring throughout the life-span of the cell. In vivo studies of reticulocyte maturation in rabbits indicate that there are multiple mechanisms of enzyme decay, and that proteolysis continues after the maturation of (morphologically recognisable) reticulocytes into young erythrocytes. Most reticulocyte hexokinase is degraded by lysosomal proteolysis, apparently triggered by an initial attack by lipoxygenase.

Adenosine Triphosphate↗
PubMed1991

Mutation analysis of glucose-6-phosphate dehydrogenase (G6PD) variants in Costa Rica.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency has previously been reported among both the black and white populations of Costa Rica. All 28 G6PD A- samples were found to be of the common G6PD A-376G/202A type. A previously described mutation associated with nonspherocytic hemolytic anemia, G6PD Puerto Limón, was found to be due to a G----A transition at nucleotide (nt) 1192, causing a glu----lys substitution. Mutations in this region of the G6PD molecule seem invariably to be associated with chronic hemolytic anemia. G6PD Santamaria had been described previously in two unrelated white subjects. We found that both did, indeed, have the same mutations. In this variant the A----G substitution at nt 376 that is characteristic of G6PD A was present, but an A----T mutation at nt 542, apparently superimposed on the ancient G6PD A mutation, resulted in an asp----val substitution. Thus, the gain of a negative charge at amino acid 126 was counterbalanced by the loss of a charge at amino acid 181, giving rise to a variant with the G6PD A mutation but with normal electrophoretic mobility.

Black People↗
PubMed1991

Some Mexican glucose-6-phosphate dehydrogenase variants revisited.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency appears to be fairly common in Mexico. We have now examined the DNA of three previously reported electrophoretically fast Mexican G6PD variants, -G6PD Distrito Federal, G6PD Tepic, and G6PD Castilla. All three of these variants, believed on the basis of biochemical characterization and population origin to be unique, have the G----A transition at nucleotide 202 and the A----G transition at nucleotide 376, mutations that we now recognize to be characteristic of G6PD A-. Two other Mexican males with G6PD deficiency were found to have the same mutation. All five have the (NlaIII/FokI/PvuII/PstI) haplotype characteristic of G6PD A -in Africa. Since the PvuII+ genotype seems to be rare in Europe, we conclude that all of these G6PD A - genes had their ancient origin in Africa, although in many of the Mexican patients with G6PD A -202A/376G the gene may have been imported more recently from Spain, where this variant, formerly known as G6PD Betica, is also prevalent.

DNA↗
PubMed1991

Galactosemia: screening and diagnosis.

Galactose is normally metabolized to glucose through the coordinated activities of three enzymes: galactokinase, galactose-1-phosphate uridyl transferase (GALT), and uridine diphospho-glucose 4-epimerase (epimerase). High concentrations of galactose and their metabolites are toxic to mammals. Hereditary deficiencies of galactokinase and of GALT and perhaps rarely of epimerase cause clinical disorders that can be prevented by early recognition and institution of a galactose-free diet. The genetics of disorders of galactose metabolisms and the methods used currently for their detection are reviewed. Future prospects in the diagnosis of these disorders are discussed.

Galactosemias↗
PubMed1991

A case of nonneurologic Gaucher's disease that biochemically resembles the neurologic types.

Systemic findings such as hepatosplenomegaly and typical Gaucher storage cells in a bone marrow aspirate led to the clinical diagnosis of Gaucher's disease in the seven-year old patient described in this report. On the basis of the lack of neurologic involvement the child was classified as having the Type 1, nonneurologic form of Gaucher's disease. After splenectomy glucocerebrosidase was extracted from her spleen for biochemical analysis. As expected, a marked deficiency of glucocerebrosidase activity was evident in the splenic extract, however her enzyme displayed anomalous behavior compared to other identical splenic preparations from documented Type 1 Gaucher's disease patients in that it failed to reconstitute with the acidic lipid phosphatidylserine. Using the polymerase chain reaction (PCR)-based color complementation assay and restriction endonuclease analysis, we compared the mutation genotype of this child with that of five other classical Type 1 patients. This analysis revealed that our patient alone was homoallelic for a T----C transition at position 1448 in the glucocerebrosidase cDNA that results in a 444Leu----Pro substitution in the glucocerebrosidase protein. The latter mutation genotype is normally associated with the neurologic phenotype, namely, the Types 2 and 3 forms of the disease. The relevance of the nature of polarity in clinical and biochemical analyses is discussed with regard to the phenotypic classification and the future clinical course of disease in the child.

Child↗
PubMed1991

Definition of the mutations of G6PD Wayne, G6PD Viangchan, G6PD Jammu, and G6PD 'LeJeune'.

We report the nucleotide (nt) substitutions of four unrelated glucose-6-phosphate dehydrogenase (G6PD)-deficient males. Only the mutation of G6PD Wayne was unique. It was a nt 769 C----G substitution causing a deduced substitution of glycine for arginine at amino acid 257. This mutation is in a region in which G6PD mutations have previously been associated with chronic hemolytic anemia. The mutation of G6PD Jammu and G6PD Viangchan were identical: a G----A mutation at nucleotide 871, predicting a Val----Met substitution at amino acid 291. However, these two variants differ with respect to the 1311 polymorphism, suggesting that they may have arisen independently. Enzyme from a child with chronic hemolytic anemia, designated G6PD 'LeJeune', proved to be due to a G----T substitution at nt 637, a change identical with that in 3 unrelated patients who had been reported previously as having G6PD Gastonia, Minnesota and Marion. These findings support the suggestion that both polymorphic and sporadic G6PD deficiency mutations in unrelated persons with G6PD deficiency are often the same, even when thought to be distinct on the basis of biochemical characterization.

Amino Acid Sequence↗