Search

Abstract: Male subjects with iron deficiency from the general population were examined for polymorphisms or sporadic mutations in TMPRSS6 to identify genetic risk factors for iron deficiency anemia. Three uncommon non-synonymous polymorphisms were identified, G228D, R446W, and V795I (allele frequencies 0.0074, 0.023 and 0.0074 respectively), of which the R446W polymorphism appeared to be overrepresented in the anemic population. In addition, three children with iron refractory iron deficiency anemia, and one sibling with iron responsive iron deficiency anemia were also examined for polymorphisms or sporadic mutations in TMPRSS6. Two children (family 1) were compound heterozygotes for a L674F mutation and a previously described splicing defect predicted to cause skipping of exon 13 (IVS13+1 G>A). One child from the second family was homozygous for a deletion (497T) causing a frameshift (L166X+36) and premature termination. The sibling and mother from the second family were compound heterozygotes for the L166X mutation and the uncommon R446W polymorphism. Although in vitro expression studies demonstrated that the R446W isoform was biologically similar to wildtype Tmprss6, clinical data indicate that the R446W produces a milder disease when carried in trans with severe mutation in Tmprss6. The four children carrying mutations in TMPRSS6 all exhibited inappropriately high urinary hepcidin levels for the degree of iron deficiency. [Copyright &y& Elsevier]

Presents information regarding the evolution of treatment for acute leukemia as of April 2001. Description of first case of leukemia in 1827; Treatment of first case of leukemia by using treatment protocols; Role of arsenic in the treatment of leukemia.

Looks at new approaches to the diagnosis and treatment of Gaucher disease, caused by an inherited deficiency of the enzyme glucocerebrosidase. Characteristics of disease; Mutations found in Ashkenazi Jews, the population in which Gaucher disease is most common; Variability in severity of disease; Effective but high-cost treatment; Risks of marrow transplant; Potential for gene transfer treatment.

Presents an overview of Gaucher's disease and informs that milder forms of the disease are found frequently, especially in the Jewish population. Autosomal recessive disorder; Cause; Population genetics; Clinical manifestations; Diagnosis; Prognosis; Genetic counseling; Treatment; Enzyme replacement; More.

Discusses enzyme glucose-6-phosphate dehydrogenase (G6PD) deficiency. Clinical importance of G6PD deficiency; Genetics and molecular biology of G6PD; Diagnosis; Screening, prevention, and treatment.

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. [ABSTRACT FROM AUTHOR]

Focuses on contribution of Janet D. Rowley to the field of science. Educational background of Janet; Her family background; Her role in studying chromosomes of leukemia patients; Awards received by Janet for her efforts in cancer research.

This article focuses on the contribution of cytogenetic researcher Susumu Ohno in the field of sex chromosome. Classical studies of Ohno on germ and somatic cells of the Norwegian rat were morphological in nature. As early as 1959 Ohno also gave consideration to the origin of the putatively inactive X-chromosome. Here he wrote: It is of extreme interest that the two X-chromosomes of the homogametic sex do not behave identically in liver cells. One exhibits outstanding positive heteropycnosis, and the other appears isopycnotic to the autosomes. At present, the explanation for this can only be conjectured. Perhaps the derivation of the X- chromosome determines whether the heteropycnotic condition is manifested during interphase and prophase. The paternally derived X- is the one expected to evidence this behavior since the male carries only a maternally derived X-chromosome. Further experimental work is necessary in order to explore this possibility.

Presents a letter to the editor about ascorbic acids.

Abstract: In 4 successive years, we investigated the seasonal and interannual variability of the total polyphenolic pool and of the individual polyphenolic compounds in Myriophyllum verticillatum, as well as their allelopathic activity in a small eutrophic lake. We tested whether nutrient availability explained interannual and seasonal changes in the production of polyphenols. There were no strong interannual variations in plant tissue carbon, nitrogen and phosphorus concentrations, while total phenolic compounds (TPC) significantly differed between years, especially in apical meristems (range: 38–122mgg−1 dry weight (DW)). Seasonal patterns, with maxima between May and July, changed between years. Partially confirming the carbon-nutrient balance hypothesis sensu Bryant et al. [Bryant, J.P., Chapin III, F.S., Klein, D.R., 1983. Carbon/nutrient balance of boreal plants in relation to vertebrate herbivory. Oikos 40, 357–368], we found correlations between TPC and the C/N (carbon/nitrogen) ratio in some but not all years, especially in apical meristems. Plant tissue phosphorus content accounted also for the variability in TPC in some years. Crude extracts of apical meristems always inhibited the growth of Anabaena variabilis, used as a target cyanobacterium. Plant TPC concentration and allelopathic activity were significantly correlated in all years except in 2005. Bioassay-directed fractionation of M. verticillatum extracts coupled with LC–MS analyses of the respective fractions revealed several isomers of HHDP-di- and -tri-galloylglucose apparently responsible for the allelopathic effects. The individual active compounds revealed a more distinct seasonal pattern compared to the pool of phenolic compounds in M. verticillatum, with a clear maximum in May, the ecologically most relevant period for inhibitory effects of submerged macrophytes on phytoplankton. [Copyright &y& Elsevier]

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/m2).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.International Journal of Obesity (2005) 29, 755–759. doi:10.1038/sj.ijo.0802954 Published online 5 April 2005 [ABSTRACT FROM AUTHOR]

Background: The gene that causes most cases of hereditary hemochromatosis is designated HFE. Three mutations exist at this locus at a relatively high gene frequency.Objective: To determine the gene frequency of the three HFE mutations and to relate genotypes to various clinical and laboratory variables.Design: Observational study.Setting: Health appraisal clinic.Patients: 10,198 adults who registered for health appraisal and consented to DNA examination for hemochromatosis. Consenting patients were slightly older and had attained a slightly higher educational level than nonconsenting patients.Measurements: Extensive medical history and laboratory tests, including complete blood count, transferrin saturation, and other chemistries; serum ferritin levels; and HFE genotype.Results: In white participants, the gene frequencies were 0.063 for the C282Y mutation, 0.152 for the H63D mutation, and 0.016 for the S65C mutation. Gene frequencies were lower in other ethnic groups. In participants with HFE mutations, the average serum transferrin saturation and ferritin levels were slightly increased, as were mean hemoglobin levels and mean corpuscular volume. A transferrin saturation of 50% had a sensitivity of only 0.52 (95% CI, 0.345 to 0.686) and a specificity of 0.908 (CI, 0.902 to 0.914) for detection of homozygosity. A ferritin level of 200 microg/L in women and 250 microg/L in men had a sensitivity of 0.70 (CI, 0.540 to 0.854) and a specificity of 0.803 (CI, 0.796 to 0.811). The prevalence of iron deficiency anemia was lower in women who carried HFE mutations.Conclusions: Screening for transferrin saturation and ferritin levels does not detect all homozygotes for the major hemochromatosis mutation. Heterozygotes for HFE mutations had a lower prevalence of iron deficiency anemia. [ABSTRACT FROM AUTHOR]

The polymerase chain reaction was used to detect four mutations in the DNA of 47 unrelated patients with type I Gaucher's disease (94 Gaucher's disease alleles). Two of the mutations, 1226 and 1448, and a new mutation (XOVR) representing cross-over between the glucocerebrosidase gene and its closely linked pseudogene, were found. There were five genotypes--namely, 1226/1226, 1226/1448, 1226/XOVR, 1226/?, and ?/? (where "?" indicates that none of the four known mutations was present). Severity of the disease was assessed with a scoring index according to age at diagnosis and extent of organ involvement. Mutation 1226 was associated with a mild clinical phenotype, and mutation 1448 with a more severe phenotype. Mutation 1226 is the most common cause of Gaucher's disease in Jewish patients. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the role of genetic testing in screening for hereditary hemochromatosis to help guide clinicians, policymakers, and researchers.Participants: An expert panel was convened on March 3, 1997, by the Centers for Disease Control and Prevention (CDC) and the National Human Genome Research Institute (NHGRI), with expertise in epidemiology, genetics, hepatology, iron overload disorders, molecular biology, public health, and the ethical, legal, and social implications surrounding the discovery and use of genetic information.Evidence: The group reviewed evidence regarding the clinical presentation, natural history, and genetics of hemochromatosis, including current data on the candidate gene for hemochromatosis (HFE) and on the ethical and health policy implications of genetic testing for this disorder.Consensus Process: Consensus was achieved by group discussion confirmed by a voice vote. A draft of the consensus statement was prepared by a writing committee and subsequently reviewed and revised by all members of the expert group over a 1-year period.Conclusions: Genetic testing is not recommended at this time in population-based screening for hereditary hemochromatosis, due to uncertainties about prevalence and penetrance of HFE mutations and the optimal care of asymptomatic people carrying HFE mutations. In addition, use of a genetic screening test raises concerns regarding possible stigmatization and discrimination. Tests for HFE mutations may play a role in confirming the diagnosis of hereditary hemochromatosis in persons with elevated serum iron measures, but even this use is limited by uncertainty about genotype-phenotype correlations. To address these questions, the expert group accorded high priority to population-based research to define the prevalence of HFE mutations, age and sex-related penetrance of different HFE genotypes, interactions between HFE genotypes and environmental modifiers, and psychosocial outcomes of genetic screening for hemochromatosis. [ABSTRACT FROM AUTHOR]

Barton JC, West C, Lee PL, Beutler E. 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. [ABSTRACT FROM AUTHOR]

Purpose: Glucose-6-phosphate deficiency is the most prevalent enzyme deficiency with an estimated 400 million people affected worldwide. This inherited deficiency causes neonatal hyperbilirubinemia, and chronic hemolytic anemia. Although most affected individuals are asymptomatic, exposure to oxidative stressors such as certain drugs or infection, can elicit acute hemolysis. The purpose of this study was to characterize the global prevalence of G6PD deficiency. Methods: We conducted a systematic review of the G6PD deficiency literature, drawing studies from various databases, including MEDLINE/Pubmed and Biosis. Selected studies included cross-sectional and longitudinal studies published between 1996 and 2006. Additionally, meta-analytic procedures were employed to assess the degree of heterogeneity amongst studies and, where appropriate, obtain pooled prevalence estimates. Results: The database searches yielded a total of 93 country-level prevalence estimates, corresponding to 76 studies. The highest prevalence rates were reported among Sub-Saharan African countries, with prevalence ranging from 13% to 28%. Among countries in the Middle East and Asia, the prevalence ranged from 1% to 20%. In the Americas and Europe, the prevalence ranged between less than one and 12%. Meta-analysis revealed a degree of heterogeneity that precluded computation of pooled global and region-level prevalence estimates. This heterogeneity in reported estimates appeared to be due to differences in G6PD deficiency assessment procedures and the years in which the studies were conducted. Conclusion: This systematic review describes the global, regional, and country-level prevalence rates of G6PD deficiency. This information is of public health import, particularly in planning programs to improve neonatal health and in the distribution of various medications, especially antimalarial drugs since G6PD deficiency is most prevalent in malaria-endemic areas. [Copyright &y& Elsevier]

Comments on the article by R. Gallanello and colleagues on the effect of Gilbert syndrome on the risk of developing hyperbilirubinaemia in Sardinian neonates. Differences in methodology in the Gallanello study which might have accounted for the discrepancies.

A letter to the editor is presented which is concerned with the inactivation of X chromosomes.