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D Rund

Publications and source records attributed to D Rund.

46 records · Page 3Linked to original sources
PubMed1991

Evolution of a genetic disease in an ethnic isolate: beta-thalassemia in the Jews of Kurdistan.

beta-Thalassemia is a hereditary disease caused by any of 90 different point mutations in the beta-globin gene. Specific populations generally carry a small number of mutations, the most common of which are those that are widely distributed regionally. The present study constitutes an extensive molecular characterization of this disease in a small, highly inbred ethnic group with a high incidence of beta-thalassemia--the Jews of Kurdistan. An unusual mutational diversity was observed. In 42 sibships 13 different mutations were identified, of which 3 are newly discovered: a C----A transversion at -88 to the cap site, a frameshift in codon 36/37, and an A----G transition in the polyadenylylation signal. Four of the mutations are unique to Kurdish Jews and have not been discovered in any other population. A fifth was found outside Kurdish Jews only in an Iranian from Khuzistan, a region bordering Kurdistan. Two-thirds of the mutant chromosomes carry the mutations unique to Kurdish Jews. We traced the origin of the mutations to specific geographic regions within Kurdistan. This information, supported by haplotype analysis, suggests that thalassemia in central Kurdistan (northern Iraq) has evolved primarily from multiple mutational events. In Turkish Kurdistan, the primary mechanism is genetic admixture with the local population. In Iranian Kurdistan, a founder effect appears to be partly responsible. We conclude that several evolutionary mechanisms contributed to the evolution of beta-thalassemia in this small ethnic isolate.

Base Sequence↗
PubMed1991

Orthopaedic trauma in men: the relative risk among drinkers and the prevalence of problem drinking in male orthopaedic admissions.

Admissions to an acute male orthopaedic ward (n = 369) were asked about their accident, their alcohol consumption, and alcohol-related problems in the past 2 years. Comparing their consumption with that of males from a community survey revealed an increased risk of orthopaedic admission in drinkers consuming 21 units of alcohol/week or over, relative to drinkers consuming less than 21 units/week, in the age group 31-50 years. In all, 34% of the sample met a criterion for problem drinking based on self-reported alcohol consumption and/or medical and social problems associated with alcohol. In 13%, alcohol was viewed by the patient as having contributed to the accident, and in 19% according to the interviewer's perception of whom 76% were classifiable as problem drinkers. Twenty-six men said the accident had made them think about changing their drinking habits. Detection of problem drinking in orthopaedic male admissions is possible and could be usefully linked to a counselling service.

Accidents↗
PubMed1990

The origin of sickle cell alleles in Israel.

Molecular genetic studies were undertaken to determine the source of chromosomes carrying the sickle cell allele in Israeli patients. Analysis of restriction fragment length polymorphism (RFLP) patterns (haplotypes) along the beta-globin gene cluster was performed on 31 sickle chromosomes obtained from 10 unrelated families living in Israel. One is a Caucasian Jewish family, recently found to be carrying the sickle allele, and the other 9 are Arab families of various communities. The Jewish family, previously noted not to carry African red blood cell markers, was discovered to have the most common African haplotype of the beta-globin gene cluster, Benin. Similarly, 8 of the Arab families were also found to carry the Benin haplotype, whereas the ninth has the CAR (Central African Republic or Bantu) haplotype. The results suggest that sickle alleles in Israel originated in Africa, probably in two different regions, and migrated north into Arab and Jewish populations.

Africa↗
PubMed1990

Intrinsic potential for high fetal hemoglobin production in a Druz family with beta-thalassemia is due to an unlinked genetic determinant.

The mechanism for elevated production of fetal hemoglobin (Hb F) in a Druze patient with beta zero-thalassemia intermedia was investigated. Heterozygous family members exhibited normal Hb F levels, suggesting that the increase in gamma-gene expression in the propositus may be partly due to anemic stress. Erythroid progenitors of these family members cultured in vitro [burst forming units (erythroid); (BFUe)] showed elevated synthesis of Hb F, indicating the existence of a genetically determined intrinsic capacity for high Hb F production in this family. The propositus was found to be homozygous for a IVS2-position 1 mutation, on the background of Mediterranean haplotype I, which is not known to be linked to high Hb F production. Moreover, extensive molecular studies of the beta-globin gene cluster, including sequence analysis of the promoter regions of the gamma-globin genes, did not reveal any cis- actin mechanism that could account for the high Hb F production in the propositus. A young niece of the propositus with beta zero-thalassemia major was recently discovered, who was homozygous for the same beta-globin allele and haplotype as the propositus. However, unlike her uncle, she does not have a high Hb F level and presents with a severe clinical course. Her inability to produce high Hb F suggests that the genetic determinant for increased gamma-gene expression in the propositus is unlinked to the beta-globin gene cluster.

Adolescent↗
PubMed1987

Regulated expression of amplified human beta globin genes.

Gene therapy for the beta thalassemias and sickle cell anemia will require high levels of expression of human beta globin genes. One method to achieve this goal is amplification of globin genes transferred into the stem cells in the bone marrow of these patients. If the amplified genes remain normally regulated, they will then further increase their expression on being induced to differentiate along an erythroid pathway. To begin this study, we constructed a plasmid containing a neomycin resistance gene, a human beta globin gene, and a wild-type DHFR cDNA, and transfected it into mouse erythroleukemia cells. All the G418-resistant clones analyzed acquired and expressed the human beta globin gene. By serial passage of the cells in increasing concentrations of methotrexate, the exogenous human beta globin genes were stably amplified in all lines, and all increased their globin mRNA expression roughly proportional to their augmented copy number. Most of the clones further increased their beta globin expression on addition of an erythroid stimulus (dimethylsulfoxide). These results indicate that globin gene amplification may be useful in increasing globin mRNA expression in further experiments whose goal is gene therapy.

Clone Cells↗
PubMed1987

Human globin gene expression after gene transfer.

Human globin genes can be transferred into mouse and human erythroid cells in culture, and can be appropriately expressed at the mRNA level in these cells. A plasmid containing a human beta globin gene is expressed in mouse erythroleukemia cells (MELC), and another containing a human epsilon or gamma gene is expressed in human erythroleukemia (K562) cells. A neomycin resistance (neoR) gene on the plasmids has been used to select for those cells containing the transferred globin genes; this selection may favor the expression of the globin genes by providing chromosomal positions requiring neoR expression. Analyzing clones resistant to G418, a neomycin analogue, demonstrated globin mRNA expression and induction. Retroviral vectors have also been used to transfer and appropriately express human beta genes in MELC. In addition, a plasmid containing a dihydrofolate reductase (DHFR) gene as well as neoR and beta globin genes has been used to amplify and express beta globin mRNA in MELC. These experiments suggest that high level appropriate expression of human beta globin genes is feasible and provides potentially useful approaches to the long-range goal of gene therapy for sickle cell anemia and beta thalassemia.

Anemia, Sickle Cell↗