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Biomedical subjects

E Beutler

Publications and source records attributed to E Beutler.

At least 19 recordsLinked to original sources
PubMed2005

Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH).

BACKGROUND: The brain endogenous cannabinoid system modulates reward and craving pathways and consequently may affect body weight. A naturally occurring missense polymorphism in the gene encoding fatty acid amide hydrolase (FAAH), the primary enzyme for inactivation of endocannabinoids, is associated with problem drug use. AIMS: To investigate the relationship between the FAAH cDNA 385 A/A (P129T) polymorphism and overweight disorders in subjects of multiple ethnic backgrounds attending a medical screening clinic. SUBJECTS: A total of 2667 subjects of white, black and Asian ancestry were genotyped and stratified by a standardized clinic-based assessment of body mass index (BMI, weight in kilograms/(height in meters)(2) or kg/m(2)). METHODS: Subjects were genotyped for the FAAH cDNA 385 C --> A polymorphism using allele-specific oligonucleotide hybridization methods by investigators blinded to all clinical information. BMI was calculated based on exact clinical measurements and World Health Organization ranges were used to stratify subjects. Statistical methods included the Fisher exact test, Mann-Whitney U-test and multivariable logistic regression analysis. RESULTS: The homozygous FAAH 385 A/A genotype was significantly associated with overweight and obesity in white subjects (P=0.005) and in black subjects (P=0.05) but not in a small group of Asians. The median BMI for all subjects was significantly greater in the FAAH 385 A/A genotype group compared to heterozygote and wild-type groups (P=0.0001). In white subjects, there was an increasing frequency of the FAAH 385 A/A genotype with increasing BMI categories of overweight (P=0.02) and obese (P=0.006) with the same trend in black subjects. CONCLUSIONS: These results suggest a role for the FAAH 385 A/A missense polymorphism as an endocannabinoid risk factor in overweight/obesity and may provide indirect evidence to support cannabinoid antagonist treatment strategies in overweight disorders.

Adult↗
PubMed2004

A previously undescribed frameshift deletion mutation of HFE (c.del277; G93fs) associated with hemochromatosis and iron overload in a C282Y heterozygote.

A 62-year-old white man with a hemochromatosis phenotype was found to be heterozygous for the C282Y mutation of the HFE gene. The H63D and S65C mutations of HFE were not present. As most C282Y heterozygotes do not develop a hemochromatosis phenotype, the coding region of the patient's HFE gene was sequenced and a previously undescribed frameshift mutation was identified in exon 2 (c.del277; G93fs) that resulted in a premature stop-codon. There were no coding region mutations of the ferroportin gene (FPN1). We performed human leukocyte antigen (HLA) typing of the patient and his brother who was heterozygous for the C282Y HFE mutation unassociated with a hemochromatosis phenotype. They shared only C282Y and the HLA haplotype A*03, B*14; hence, the c.del277 mutation was linked to the HLA haplotype A*02, B*44 and therefore not on the same chromosome as the C282Y mutation. Thus, the present patient's only intact HFE protein is C282Y, and this may explain his hemochromatosis phenotype.

Amino Acid Sequence↗
PubMed2002

A previously undescribed nonsense mutation of the HFE gene.

A patient with clinically manifest hereditary hemochromatosis was found to be heterozygous for the c.845 A-->G (C282Y) mutation. As simple heterozygotes for this mutation do not develop the hemochromatosis phenotype, the coding region of the patient's HFE gene was sequenced and a previously undescribed nonsense mutation was identified at c.211 C-->T (R74X). The patient's brother who also had the hemochromatosis phenotype shared his HFE genotype. To determine how common such mutations might be, the coding and 5' region of the HFE genes of 11 subjects who had been found in a large population survey to be heterozygous for the C282Y mutation and had elevated ferritin levels were sequenced. No mutations were found. Sequencing of the HFE gene also revealed two polymorphisms that had not previously been noted, -467 C-->G and -970 T-->G. Neither of these mutations appear to cause an abnormality in iron metabolism.

Codon, Nonsense↗
PubMed2002

A chimeric mouse model of Gaucher disease.

BACKGROUND: There is a major need for a mouse model of Gaucher disease, but the glucocerebrosidase knockout mouse is not viable; it dies shortly before or immediately after birth, apparently because of involvement of the central nervous system and/or skin. The most common form of Gaucher disease, type I, has a phenotype that is limited to the monocyte-macrophage system. MATERIALS AND METHODS: We have created a chimeric mouse by infusing hematopoietic stem cells from fetuses that are homozygous for the glucocerebrosidase knockout into irradiated mice. RESULTS: The chimeric mice manifested a severe deficiency of glucocerebrosidase activity in peripheral blood cells and spleen indicating a lack of cell-cell correction. Levels of glucocerebroside in spleen and liver are increased, and infusing the mice with exogenous glucocerebroside/albumin particles produced a marked increase in the amount of glucocerebroside stored in liver and spleen. Morphologically identifiable Gaucher cells were not present. CONCLUSIONS: The chimeric model reflects the increased glycolipid storage in the reticuloendothelial system that is characteristic of Gaucher disease, and could be useful as a model for studying treatment of Gaucher disease.

Animals↗
PubMed2001

Discrepancies between genotype and phenotype in hematology: an important frontier.

An African American male infant with sickle cell disease has a devastating stroke; an African American soldier is surprised when he is informed that he has sickle cell disease. They are both homozygous for the same mutation. An Ashkenazi Jewish woman with Gaucher disease has a huge spleen and severe thrombocytopenia; her older brother, homozygous for the same 1226G glucocerebrosidase mutation, is found on routine examination to have a barely palpable spleen tip. The fact that clinical manifestations of genetic diseases can vary widely among patients has been recognized for many decades. In the past, however, it could often be attributed to the pleomorphic nature of mutations of the same gene: the patient with severe disease, it was averred, must have a different mutation than the one with mild disease. Even before a precise definition of mutations could be achieved at the DNA level, such an explanation did not serve to clarify the differences that existed between siblings with the same autosomal recessive disease. Such siblings must surely be carrying the same 2 disease-producing alleles. With the advent of sequence analysis of genes, the great extent of phenotype variation in patients with the same genotype has come to be more fully appreciated, but understanding of why it occurs continues to be meager. It is the purpose of this review to explore some of the variations in phenotype seen by hematologists in patients with identical mutations, to indicate where some progress has been made, and to suggest how understanding in this important area may be expanded.

Animals↗
PubMed2001

Large-scale molecular screening for galactosemia alleles in a pan-ethnic population.

DNA samples from 4,796 subjects from diverse ethnic groups were screened for five frequently encountered galactose-1-phosphate uridyl transferase (GALT) mutations: S135L (cDNA nt 404C-->T, as numbered from the initiator ATG codon, with A=1); Q188R (cDNA nt 563A-->G); K285 N (cDNA nt 855G-->T); the Duarte variant, N314D (cDNA nt 940A-->G); and the Los Angeles variant, which contains L218L (cDNA nt 652C-->T) and N314D. Among Whites, the gene frequency of the Q188R mutation was 0.29%, and that of the K285 N mutation was 0.062%. Only one S135L mutation was encountered among 505 African-Americans (gene frequency 0.10%). The pan-ethnic gene frequencies of the Duarte and the Los Angeles variants were 5.1% and 2.7%, respectively. Both of these frequencies were significantly less among African-Americans and Asians than among Whites and Hispanics. Native Americans revealed a higher incidence of the both variants. Based upon the gene frequency of the Q188R mutation in the White population, the birth incidence of classic galactosemia is estimated at one patient per 47,000 in the White population. This prevalence would be increased by inbreeding. It agrees well with the results from newborn screening programs and is only minimally higher than that reported in most studies, suggesting that most, if not all, infants with the galactosemia genotype are born and survive sufficiently long to be screened.

Alleles↗
PubMed2001

Hereditary non-spherocytic haemolytic anaemia due to red blood cell glutathione synthetase deficiency in four unrelated patients from Spain: clinical and molecular studies.

In four unrelated patients with chronic haemolysis and markedly reduced red blood cell (RBC) glutathione (49.5%, 12.6%, 11.5% and 15% of the normal concentration respectively), a severe glutathione synthetase (GSH-S, EC 6.3.2.3) deficiency was found. One case exhibited a neonatal haemolytic anaemia associated with oxoprolinuria, but without neurological manifestations. The family study revealed GSH-S activity in both parents to be around half the normal level, a finding consistent with the presumed autosomal recessive mode of inheritance of this enzymopathy. Two cases exhibited a well-compensated haemolytic syndrome without anaemia or splenomegaly at steady state. One of these cases was diagnosed after an episode of acute haemolytic anaemia after fava bean ingestion. The remaining patient suffered from moderate to severe chronic non-spherocytic haemolytic anaemia and splenomegaly, and required occasional blood transfusion for a haemolytic crisis associated with drug ingestion. In this patient, the anaemia was corrected by splenectomy. In addition to GSH-S, a panel of 16 other RBC enzyme activities was also studied in all the patients. Hexokinase, aldolase, glucose-6-phosphate dehydrogenase and pyruvate kinase activities all increased; these increases were to be expected, given the rise in the number of circulating reticulocytes. In two patients, the incubation of RBCs with hydrogen peroxide revealed an enhanced production of malonyldialdehyde. DNA analysis showed a homozygous state for 656 A-->G mutation in patients 2 and 3. The GSH-S gene of patient 1, studied elsewhere, revealed an 808 T-->C. The GSH-S gene of patient 4 was not available for study. The present study demonstrates that GSH-S deficiency is also present in Spain and further supports the molecular and clinical heterogeneity of this enzymopathy

Adult↗
PubMed2001

Human transferrin G277S mutation: a risk factor for iron deficiency anaemia.

Numerous polymorphisms of the transferrin gene result in a range of electrophoretic variants. We show that one of these mutations has a functional consequence. A G-->A mutation at cDNA nucleotide 829 (G277S) was associated with a reduction in total iron binding capacity (TIBC). In menstruating white women, the G277S genotype was a risk factor for iron deficiency anaemia: iron deficiency anaemia was present in 27% of homozygous G277S/G277S women, 10% of G277G/G277S heterozygous women and 5% of homozygous wild-type G277G/G277G women.

Adult↗