Presentation of the George M. Kober Medal to Victor A. McKusick.
Explore the source record for details and available documents.
Awards and Prizes↗
Biomedical subjects
D J Weatherall
Publications and source records attributed to D J Weatherall.
Clinical features and molecular analysis of the alpha thalassemia/mental retardation syndromes. II. Cases without detectable abnormality of the alpha globin complex.
We have identified five unrelated patients, all of north European origin, who have hemoglobin H (Hb H) disease and profound mental handicap. Surprisingly, detailed molecular analysis of the alpha globin complex is normal in these subjects. Clinically, they present with a rather uniform constellation of abnormalities, notably severe mental handicap, microcephaly, relative hypertelorism, unusual facies and genital anomalies. Hematologically, their Hb H disease has subtly but distinctly milder properties than the recognized Mendelian forms of the disease. These common features suggest that these five "nondeletion" patients have a similar underlying mutation, quite distinct from the 16p13.3 deletion associated with alpha thalassemia and mild to moderate mental retardation described in the accompanying paper. We speculate that the locus of this underlying mutation is not closely linked to the alpha globin complex and may encode a trans-acting factor involved in the normal regulation of alpha globin expression.
Adolescent↗
The molecular basis of beta-thalassemia in Thailand: application to prenatal diagnosis.
To enable the prenatal diagnosis of beta-thalassemia by direct detection of the mutant beta-globin genes, we have determined the spectrum of mutations causing this disease in Thailand. The techniques employed included a combination of synthetic oligonucleotide probe hybridization, direct sequencing of genomic DNA enzymatically amplified by the polymerase chain reaction, and cloning and sequencing of the beta-globin genes. A total of 116 beta-thalassemia genes from 78 Hb E/beta-thalassemia patients and from 19 homozygous beta-thalassemia patients were analyzed, and the mutation was characterized in 112/116 (97%) of them. Eleven mutations were found, of which four (-CTTT in codon 41/42, AAG----TAG in codon 17, C----T in position 654 of the IVS-2 region, and A----G in position -28 upstream of the beta-globin gene) accounted for 83%; two previously undescribed mutations have been identified. The spectrum of beta-thalassemia mutations is similar to that reported among the Chinese. However, within the Thai population itself, patients with homozygous beta-thalassemia show a wider spread of mutations in comparison with the Hb E/beta-thalassemia group, in whom the frameshift 41/42 mutation predominates at a frequency of 62%. This difference in distribution may reflect the difference in ethnic origin of the two groups. Characterization of these mutations should aid the planning of a prenatal diagnosis program for beta-thalassemia in Thailand.
Base Sequence↗
Detection of breakpoints in submicroscopic chromosomal translocation, illustrating an important mechanism for genetic disease.
A 3-year-old boy presented with alpha-thalassaemia, dysmorphic features, and mental handicap. His younger sister is also mentally retarded, but haematologically normal. High resolution cytogenetic analysis revealed a normal karyotype in all family members. However, a combination of DNA analysis and in situ hybridisation demonstrated that the mother has a previously unsuspected balanced reciprocal translocation between the tips of the short arms of chromosomes 1 and 16, and that the alpha-globin gene complex (which maps to the tip of chromosome 16) is included in the translocated segment. Both of her children have inherited one of the translocation chromosomes in an unbalanced fashion: the boy has the derived chromosome 16, and therefore has alpha-thalassaemia, whilst the girl has the derived chromosome 1. Such cytogenetically invisible subtelomeric translocations are probably an important and hitherto unrecognised cause of genetic disease.
Alpha-Globulins↗
The frequency and origin of the sickle cell mutation in the district of Coruche/Portugal.
The frequency of the beta S mutation in the district of Coruche/Portugal is estimated to be about 4% from analysis of a group of 181 school children and their teachers in an area in which malaria has been endemic until recently. Several white Portuguese patients with sickle cell disease (six homozygous SS and one S beta degree thalassaemia) were found in a group of 309 further patients who were known and followed up by local medical practitioners. These patients had clinical and haematological features similar to patients of African origin, although their growth and sexual development appeared to be normal. The analysis of an array of polymorphic restriction sites within the beta S globin gene cluster (beta S haplotype) showed patterns that are known to occur in Africa. The frequencies of the three main African beta S haplotypes termed Senegal, Bantu, and Benin reflect the extent of Portuguese naval explorations. It is concluded that the sickle cell gene in Portugal has probably been imported from Africa and has been amplified in comparison with other genes characteristic for African races because of the selective advantage of AS heterozygotes in an area endemic for malaria.
Adolescent↗
Antibody-dependent red cell removal during P. falciparum malaria: the clearance of red cells sensitized with an IgG anti-D.
The clearance of autologous red cells sensitized with an IgG anti-D has been studied in patients during and after an attack of P. falciparum malaria, and in 11 uninfected control subjects. In most patients with P. falciparum malaria there was evidence of increased clearance of sensitized red cells, compared to controls. Clearance half-times of IgG sensitized red cells were significantly decreased (P less than 0.01) in 16 patients with acute falciparum malaria (median 21 min, range 11-53 min) compared to 11 control subjects (median 37 min, range 20-60 min). This difference was independent of the degree of IgG sensitization of red cells. In patients with acute falciparum malaria, clearance half-times were positively correlated with venous haematocrit (P less than 0.05). In 11 patients studied between 1 and 9 weeks after the attack, clearance half-times (median 17 min, range 11-56 min) were also significantly decreased compared to controls (P less than 0.01). In the majority of acute and convalescent patients, there was further evidence for early destruction of an additional substantial proportion of sensitized red cells. Our data indicate that in most patients with uncomplicated P. falciparum malaria, IgG sensitized red cells are rapidly removed from the peripheral circulation by the spleen, and that rapid clearance persists during recovery.
Adolescent↗
A non-deletion hereditary persistence of fetal hemoglobin (HPFH) determinant not linked to the beta-globin gene complex.
We describe an Asian Indian family with a non-deletion form of hereditary persistence of fetal hemoglobin (HPFH) and beta zero thalassemia. The propositus who has homozygous beta zero thalassemia has an unusually mild form of the disease which is ascribed to the co-inheritance of HPFH. The interaction of HPFH and beta thalassemia was studied in five generations of this family. Linkage analysis showed that the genetic determinant for the HPFH segregates independently from the gamma delta beta globin gene complex. Analysis of HPFH linkage to a panel of genetic markers in such a large family offers the possibility of defining a transacting locus (or loci) involved in the expression of the gamma globin gene.
Adolescent↗
The spectrum of beta-thalassaemia in Burma.
The molecular defects causing beta-thalassaemia (beta-thal) have been analyzed in 63 unrelated Burmese patients. The patients include 49 with Hb E/beta-thal, 13 with beta-thal major and 1 with Hb S/beta-thal. Using synthetic oligonucleotide probes and aided by the polymerase chain reaction 64/76 (84%) of the alleles have been characterized. To date 6 mutations have been identified. The most common mutation is the splicing defect at IVS-1 nt 1 which accounts for 32% of the alleles. Complete characterization of these alleles should aid the initiation of a prenatal diagnosis programme for beta-thalassaemia in the Burmese population.
Alleles↗
A review of the molecular genetics of the human alpha-globin gene cluster.
Explore the source record for details and available documents.
Base Sequence↗
Prenatal diagnosis of the major haemoglobin disorders.
Explore the source record for details and available documents.
Anemia, Sickle Cell↗
Molecular characterization of a high A2 beta thalassemia by direct sequencing of single strand enriched amplified genomic DNA.
Two families, one of Anglo-Saxon-Dutch descent, and the other, West Indian black, have an atypical beta thalassemia characterized by an unusually high level of Hb A2 in the heterozygous state. Restriction endonuclease mapping showed a deletion of about 1.35 kilobase (kb) in the 5' region of the beta globin gene. Direct sequencing of a specific region of genomic DNA amplified by a new modification of the polymerase chain reaction defined the deletion to be 1,393 base pairs (bp) and to be the same in both families. The deletion extends from 485 bp 5' to the mRNA CAP site to the middle of the second intervening sequence. This deletion, together with three others previously described that remove the 5' end of the beta gene but leave the delta gene intact, are all associated with unusually high levels of Hb A2 in the heterozygous state.
Base Sequence↗
Genetic factors as determinants of infectious disease transmission in human communities.
Genetic factors may play an important role in individual susceptibility to infection. Hitherto this problem has been investigated by attempting to relate the distribution of genetic polymorphisms in populations to present or past infection, or by analysing specific infections by classical twin studies or group comparisons. There is reasonable evidence that the common red-cell polymorphisms involving haemoglobin, enzymes or membrane have been maintained by relative resistance to malaria. Blood-group heterogeneity, including secretor status, may reflect varying susceptibility to bacterial, virus and yeast infection. There is increasing evidence that the HLA-DR system may be involved in modifying the clinical course of bacterial, virus and parasitic infection. So far no specific resistance or susceptibility loci similar to those found in murine models have been found in man. DNA analysis, particularly involving restriction fragment length polymorphism associations with candidate genes, offers a valuable new approach to this problem.
Communicable Diseases↗
A highly conserved amino-acid sequence in thrombospondin, properdin and in proteins from sporozoites and blood stages of a human malaria parasite.
As a consequence of gene cloning and DNA sequencing several gene families are emerging in the field of cell-cell recognition. These include immunoglobulins, integrins, certain extracellular glycoproteins and a family of functionally unrelated proteins which include factor B. We report here the cloning and sequencing of a gene from Plasmodium falciparum, coding for a protein we call thrombospondin related anonymous protein (TRAP), which shares certain sequence motifs common to other well-characterized proteins. The most significant homology is based around the sequence Trp-Ser-Pro-Cys-Ser-Val-Thr-Cys-Gly (WSPCSVTCG), present in three copies in region I of thrombospondin (TSP), six copies in properdin (P) and one copy in all the circumsporozoite (CS) proteins sequenced so far. TRAP also shares with certain extracellular glycoproteins, including TSP, the cell-recognition signal Arg-Gly-Asp (RGD), which has been shown to be crucial in the interaction of several extracellular glycoproteins with members of the integrin superfamily. Unlike the CS protein, TRAP is expressed during the erythrocytic stage of the parasite life cycle.
Amino Acid Sequence↗
Isolation and immunocytochemical characterization of human bone marrow stromal macrophages in hemopoietic clusters.
Stromal macrophages (M phi) have been localized in situ and isolated within erythroid clusters from human marrow. Stromal M phi arborize in an extensive network uniformly distributed throughout marrow interstitium, and express the phenotype CD4+, CD11a+, CD11c+, CD13+, CD14+, CD16+, CD18+, CD31+, CD32+, FcRI+, HLA-DR+, and CD35-, transferrin receptor-negative, and CD11b (weak). They express endocytic receptor antigens, but show significant differences in myeloid antigen expression compared with freshly harvested or cultured monocytes. Human stromal M phi are therefore specialized mature marrow M phi that are accessible for further investigations in infectious, storage, or hemopoietic disorders.
Antibodies, Monoclonal↗
A second genetic locus for autosomal dominant polycystic kidney disease.
Hitherto, mutations that lead to autosomal dominant adult-type polycystic kidney disease have been found to be linked to the alpha-globin genes on the short arm of chromosome 16. In an Italian family, absence of linkage between the disease mutation and alpha-globin indicates that the condition can be caused by mutations in a second gene. The clinical features of the disease in this Italian family are indistinguishable from those found in the "linked" families. The finding that there are two polycystic kidney disease genes means that linkage must be demonstrated independently in each family before predictive tests with DNA probes can be used reliably.
Adult↗
The role of cloned genes in the prevention of genetic disease.
The application of recombinant DNA technology to the study of human genetic disease promises to increase the scope for carrier detection and prenatal diagnosis. Here we summarize current experience with prenatal diagnosis of single-gene disorders by DNA analysis and highlight some of the technical and organizational problems that remain to be solved.
Cloning, Molecular↗