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Biomedical subjects

E Beutler

Publications and source records attributed to E Beutler.

At least 109 records · Page 6Linked to original sources
PubMed1996

Glucocerebrosidase (Gaucher disease).

Gaucher disease is the most common glycolipid storage disorder, characterized by storage of the glycolipid, glucocerebroside in the liver, spleen, and marrow. The most prevalent form of Gaucher disease is designated type I (MIM 230800). Patients with type I disease may have hepatomegaly, splenomegaly, bone lesions, and less commonly, lung disease, but are free of neurological involvement. Types II (MIM 230900) and III (MIM 2310000), the acute infantile and juvenile forms, respectively, of Gaucher disease, are characterized by the fact that the central nervous system is affected.

Alternative Splicing↗
PubMed1996

The 1591C mutation in triosephosphate isomerase (TPI) deficiency. Tightly linked polymorphisms and a common haplotype in all known families.

In order to investigate the basis of the repeated occurrence of the 1591C mutation (TPI 1591C, 105 Glu-Asp) in multiple unrelated families throughout the world, we studied five microsatellite and short tandem repeat markers that lie within a 1.77 megabase region which includes the TPI gene. We also studied an intragenic polymorphic marker that lies within intron 5 of the TPI gene. This polymorphism, recently described by others, is characterized by either an A or a G at position 2262 (the A in the initiation ATG is designated as +1 for both genomic and cDNA nucleotides). With very minor exceptions, all of the known families in the world with the 1591C mutation were available for study. These included five families from the U.S., three from France, one from Greece, one (of Turkish origin) from Germany, and two from Australia. Although we did not have the opportunity to directly study five families from the U.K., key data concerning the 2262 intragenic polymorphism in these subjects were made available to us. Four of the microsatellite and short tandem repeat markers were linked, but in apparent equilibrium. In contrast, a polymorphic repeat pentamer in the CD4 gene, thought to lie telomeric to TPI, was in apparent complete linkage disequilibrium with the TPI 1591C mutation. The intragenic polymorphism was also in apparent complete linkage disequilibrium with the mutation. In unrelated persons of known phase (1591C homozygotes or normal controls), the comparative allele frequencies for the CD4 pentameric repeat were 1.0 (14/14 alleles) in homozygous TPI 1591C subjects and 0.412 (28/68 alleles) in normal subjects (p < 0.0001). Again, in persons of known phase, the comparative allele frequencies for the A form of the intragenic 2262 A or G polymorphism were 1.0 (14/14 alleles) in 1591C homozygotes and 0.130 (7/54 alleles) in normals (p < 0.0001). Haplotypes were discernible in all of the 1591C homozygotes and in several of the heterozygotes and normals. The CD4 162, TPI 2262A haplotype was found on only two of thirty-eight normal chromosomes, but was universally associated with 1591C. The data indicate that all TPI 1591C subjects are descendants of a common ancestor who probably lived in what is now England or France. The original mutation probably occurred well in excess of 1000 years ago.

Australia↗
PubMed1996

Mutation analysis in hereditary hemochromatosis.

The DNA of 147 patients of European origin clinically diagnosed with idiopathic hemochromatosis and 193 controls was examined for mutations of the HLA-H gene at nt 845 and nt 187. One hundred twenty-one (82.3%) of the hemochromatosis patients were homozygous and 10 (6.8%) heterozygous for the 845A (C282Y) mutation. All of the homozygous patients were also homozygous for nt 187C, and all 845A heterozygotes had at least one copy of 187C. Thus, the nt 845 and nt 187 mutations were in complete linkage disequilibrium; nt 187 was a C on all chromosomes with the 845A mutation. Eight of the 10 heterozygotes for 845A were heterozygous for 187G(H63D). The excess of heterozygotes at both nt 187 and nt 845 suggested either the presence of as yet undiscovered mutations existing in trans with 845A and in linkage disequilibrium with 187G, or that the 187G itself is a deleterious mutation, which in concert with the 845A can give rise to hemochromatosis. None of the 193 normal controls were homozygous for 845A and 29/193 (15%) were heterozygous for 845A. Although 47/193 (24.3%) of normal controls were heterozygous for the 187G mutation only two of these carried the 845A mutation. If the 187G mutation complemented the 845A mutation with high penetrance in causing hemochromatosis, then the population frequency of the two genes would require that a high proportion of patients with hemochromatosis be heterozygous for 845A and 187G. Instead, the frequency of homozygotes for the 845A mutation was much higher than that of the 845A/187G genotype. Based on our data, the penetrance of the 845A/187G genotype is only 1.5% and based on the data of Feder et al. only 0.5%. In contrast, the penetrance of the homozygous 845A/845A genotype seems to be very high. Thus, screening for this genotype should be very useful.

Alleles↗
PubMed1996

A comparison of two neurologic scoring instruments for multiple sclerosis.

We examined the degree of association between two neurologic impairment scales, the Extended Disability Status Scale (EDSS) and the Scripps Neurologic Rating Scale (SNRS), with data from a randomized, double-blind, placebo-controlled clinical trial assessing the safety and efficacy of cladribine as treatment for chronic progressive multiple sclerosis (MS). We found that the EDSS and SNRS were not strongly correlated within individual patients, contrary to expectation; moreover, in 9 of the 48 evaluable patients, the directions of their changes from baseline values were not mutually consistent. The scales were differentially sensitive to clinical changes over time, with the EDSS indicating a more abrupt, and the SNRS a more gradual, change in the clinical course of disease. The validity of different impairment scales, and their sensitivity to detect clinical changes, should be formally assessed in future clinical trials using these scales as outcome measures.

Adult↗
PubMed1996

G6PD: population genetics and clinical manifestations.

The glucose-6-phosphate dehydrogenase (G6PD) gene is X-linked. There are numerous mutations that cause a deficiency of this enzyme in erythrocytes. G6PD deficiency can produce anemia, both when drugs are administered and under the stress induced by infection. Functionally severe variants cause hereditary non-spherocytic hemolytic anemia, i.e. anemia even in the absence of stress. Neonatal jaundice occurs in G6PD deficiency, but it is likely that it is largely due to impairment of liver function, rather than to hemolysis. It has been suggested that there are clinical manifestations of G6PD deficiency that are related to other tissues, but the existence of these is not well documented. Some mutations that produce G6PD deficiency in red cells exist at polymorphic frequencies. Individuals with such mutations seem to have enjoyed a selective advantage because of resistance to falciparum malaria. Different mutations, each characteristic of certain populations, are found, and have been characterized at the deoxyribonucleic acid (DNA) level. G6PD A-(202A376G) is the most common African mutation. G6PD Mediterranean(563T) is found in Southern Europe, the Middle East and in the Indian subcontinent. Several other mutations are common in Asia. Genetic variability of G6PD has played an important role in the understanding of a variety of developmental processes.

Africa↗
PubMed1996

Neonatal jaundice in Saudi newborns with G6PD Aures.

Sixty-five of 3261 (2%) Saudi neonates were found to be severely G6PD-deficient during a cord blood screening programme conducted from April to December, 1992. However, at the time of molecular studies, the blood samples were available from only 20 randomly selected children, aged from 1 to 6 years. DNA analyses showed that seven (three boys, four girls) of these 20 (35%) had G6PD Aures (nt 143 T - > C), a variant associated with favism which was recently reported in an Algerian. Twelve carried the G6PD Mediterranean (563 T) mutation, and in one child the mutation remained unidentified. The medical records of these children showed that all who had G6PD Aures, including a premature baby, were jaundiced during the 1st week of life, but only six full-term infants had moderate-to-severe hyperbilirubinaemia. Two of seven babies had seizures and one of these two developed kernicterus, in spite of timely blood transfusion.

Base Sequence↗
PubMed1996

Development of cladribine treatment in multiple sclerosis.

Cladribine is a new type of drug with properties of selective lymphocyte suppression that appear to favorably alter the clinical course of progressive multiple sclerosis (MS). The history of the development of cladribine treatment in chronic progressive MS is discussed, and the application of cladribine treatment to progressive multiple sclerosis in a double-blind, placebo crossover study is reviewed. Cladribine selectively targets both resting and dividing lymphocytes and may be able to destroy the activated lymphocytes that induce CNS demyelination, thus producing stabilization or improvement in chronic MS. Although the role of cladribine has not yet been fully defined, additional studies are underway to evaluate the efficacy and safety of cladribine in both progressive MS and relapsing-remitting MS.

Cladribine↗
PubMed1996

Gaucher disease: four families with previously undescribed mutations.

We describe four families with patients with type I Gaucher disease exhibiting previously undescribed mutations of the glucocerebrosidase gene. We found Cherokee Indian woman to have a G-->C substitution in cDNA nucleotide 354, predicting a lysine-->aspargine substitution in amino acid 79 of the processed protein. In a Greek family, we found an allele with a C-->T substitution in nucleotide 475 giving rise to an arginine-->tryptophan substitution at amino acid 120. In another non-Jewish European patient, we identified a C-->T substitution in nucleotide 1223, predicting a threonine-->methionine mutation in amino acid 369. We found two non-Jewish European children to have a C-->T mutation at nucleotide 1357, predicting termination at codon 414. Although siblings carry the same two glucocerebrosidase mutations, in these families as in others we noted considerable differences in severity of clinical manifestations. Finding the reason for these differences is an important goal in the study of Gaucher disease.

Adult↗
PubMed1995

Human glucose phosphate isomerase: exon mapping and gene structure.

The structure of the gene for human glucose phosphate isomerase (GPI) has been determined. Three GPI clones were isolated from a human genomic library by using a full-length GPI cDNA probe and were characterized. Oligonucleotides based on the known cDNA sequence were used as primers in amplification and sequence analyses. This led to the identification of the exon-intron junctions. By this approach, 18 exons and 17 introns have been identified. The exons range in size from 44 to 431 nucleotides. The intronic sequences surrounding the exons provide useful information for the identification of mutations that give rise to human GPI deficiency associated with chronic hemolytic anemia.

Amino Acid Sequence↗
PubMed1995

Erythrocyte fragility and chronic intermittent pigmenturia in a dog.

A 2-year-old spayed female Shetland Sheepdog had recurrent episodes of discolored urine. Treatments administered for presumed urinary tract infection did not prevent recurrence. Episodes of pigmenturia appeared to correlate with stressful situations or excessive activity. Examination of urine sediment consistently revealed that RBC were not evident, despite a positive result for blood on urinalysis. This was suggestive of hemoglobinuria, and diagnostic testing was instituted to determine the underlying cause. Results of alkaline and osmotic fragility tests were useful in determining that an increase in erythrocyte fragility was the underlying cause of the recurrent pigmenturia. Erythrocyte fragility testing should be considered in animals that do not respond to appropriate treatments for pigmenturia.

Animals↗
PubMed1995

Glucose-6 phosphate dehydrogenase mutations and haplotypes in various ethnic groups.

Mutations that produce glucose-6-phosphate dehydrogenase (G6PD) deficiency have been identified in samples from patients with hemolytic disease in the United States, and in G6PD-deficient samples from Greece, the Canary Islands, the Czech and Slovak Republics, South China, and in samples from the Coriell Cell Repository. Eight new mutations are described. Particularly unusual were a nonsense mutation ("G6PD Georgia"1284A), a deletion of six bases ("G6PD Stony Brook" 724-729 del) coding for two amino acids, and a deletion of the invariant dinucleotide ApG at the 3' acceptor splice site in the highly conserved sequence between intron 10 and exon 11 ("G6PD Varnsdorf"). In addition, five new missense point mutations were identified: "G6PD Cleveland"820A creates a deduced AA 274 Glu-->Lys; "G6PD West Virginia"910T AA 303 Val-->Phe; "G6PD Fushan"1004A, AA 335 Ala-->Asp; "G6PD Olomouc"1141C AA 381 Leu-->Phe; and "G6PD Praha"1166G AA 389 Glu-->Gly. All of the new mutations except for "G6PD Fushan"1004A were found in patients with hereditary nonspherocytic hemolytic anemia. A coincidental finding in the case of G6PD "West Virginia" was a C-->T transition at nucleotide 1,191. This silent mutation, Asn-->Asn, appears to be rare. Haplotype analysis of mutations in samples from the Canary Islands and South China agreed with previous findings.

Anemia, Hemolytic↗
PubMed1995

Triosephosphate isomerase deficiency: repetitive occurrence of point mutation in amino acid 104 in multiple apparently unrelated families.

The molecular basis of triosephosphate isomerase (TPI) deficiency was studied in 3 patients from three separate families. In all 3 patients, genomic DNA directly sequenced after amplification by the polymerase chain reaction exhibited the point mutation TPI315C amino acid 104 Glu-->Asp. Although other mutations known to cause TPI deficiency have been restricted to single families, the amino acid 104 defect has now been described in nine apparently unrelated families throughout the world and is clearly the most frequently occurring form of the disorder. The basis of the repetitive occurrence of this mutation remains unexplained.

Anemia, Hemolytic↗