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Biomedical subjects

E D du Toit

Publications and source records attributed to E D du Toit.

At least 19 recordsLinked to original sources
PubMed1999

Allelic diversity of the human plasma alpha(1,3)fucosyltransferase gene (FUT6).

The 1080-bp coding region of the human plasma alpha(1,3)fucosyltransferase gene (FUT6) was sequenced in a total of 161 individuals (322 chromosomes) drawn from three populations, involving 56 Africans (Xhosa), 52 European-Africans of South Africa, and 53 Japanese. In addition to six reported base substitutions, eleven new base substitutions and a single base insertion were found in the coding region of the FUT6. Eleven functional and four null alleles were encountered, of which 10 alleles were novel alleles identified in this study. Two null alleles have been identified previously, whereas two novel null alleles, which contained a single base (cytosine) insertion at nucleotide 499, were found in a Xhosa population. The allelic distributions of FUT6 were different among these three populations. The heterozygosity of FUT6 was 0.860, 0.699, and 0.632, in Xhosa, European-African (South Africa), and in Japanese populations, respectively. The extensive DNA sequence diversity of the FUT6 may be suitable for application as a tool in genetic studies for modern human evolution.

Alleles↗
PubMed1998

Extensive polymorphism of the FUT2 gene in an African (Xhosa) population of South Africa.

The human secretor type alpha(1,2)fucosyltransferase gene (FUT2) polymorphism was investigated in Xhosa and Caucasian populations of South Africa by polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing. Six new base substitutions were found in the coding region of FUT2. A single base (C) deletion at nucleotide 778, which led to a frame shift and produced a stop codon at codon 275, was responsible for the enzyme inactivation. Three nonsynonymous base substitutions, A40G (lle14Val), C379T (Arg127Cys), and G481A (Asp161Asn), and two synonymous base substitutions, A375G (Glu125) and C480T (His160), were also identified in functional alleles. As a result, seven new alleles, Se40, Se481, Se40,481, Se357,480, Se357,379,480, Se375, and se357,480,778 were identified. Population studies revealed that an allele containing a nonsense mutation G428A (Trp143stop) (se428) was the common null allele in both Xhosa and Caucasian populations, whereas an allele containing a missense A385T (Ile129Phe) mutation (se357,385), which is the common null allele in Orientals, was found to be absent from both populations. The heterozygosity rates of FUT2 genotypes were as high as 0.75 in the Xhosa population and 0.65 in the Caucasian population. Therefore, the extensive polymorphism and race specificity of the FUT2 gene make it suitable for application as a new tool in genetic studies of modern human evolutionary history.

Alleles↗
PubMed1997

The absence of DR51 in a DRB5-positive individual DR2ES is caused by a null allele (DRB5*0108N)

DR51, a protein encoded by the DRB5 gene, was shown to be present in almost all DR2-positive haplotypes. Exceptions were reported, some DR2-negative samples were shown to be DR51 positive and in a number of DR2-positive samples no DR51 antigen could be demonstrated. In some of them lack of the DRB5 gene was the cause of the absence of DR51 but in others the DRB5 gene was present without resulting in a detectable gene product. Many of these variants were studied in detail in previous international workshops. One of them was DR2ES from our laboratory. She is a DR15-positive DR51-negative individual of oriental origin with a clearly demonstrable DRB5*01 allele when typed by molecular techniques. To unravel the molecular mechanism responsible for the defect in expression, cDNA and DNA encoding the defective DRB5 allele were analyzed. Nucleotide sequence analysis of exon 2 showed no differences from the sequence of DRB5*0102. However, when exon 3 was examined a difference in length was noticed due to a deletion of 19 nucleotides between codon 161 and 168. The deletion caused a frameshift and a premature stopcodon resulting in a null allele. The same allele could be demonstrated in 6 other unrelated individuals of oriental origin as well as in 5 individuals from South Africa. The absence of the DR51 protein was explained by the presence of an alteration in the DRB5 allele resulting in a null allele. The allele has been officially named DRB5*0108N. This is the first description of a null allele of the DRB5 gene.

Alleles↗
PubMed1996

C4 polymorphism and extended HLA haplotypes in Namibian San and Khoi and in South African Xhosa.

We studied C4A and C4B polymorphisms and HLA-B and -DR associations in the San, Khoi and Xhosa. C4A and C4B alleles were determined using conventional protein allotyping methods. The C4A*3, C4B*1 haplotype had a high frequency (30-55%) in all populations. The frequency of C4A*3, C4B*Q0 was 7-19%. The C4A*Q0, C4B*1 haplotype was frequent (15%) in the Khoi but very rare in the San (P < 0.001). C4A*12 A*91, C4B*Q0 was frequent in the Xhosa (15%) but rare in the San and Khoi (P < 0.001). Alleles C4A*5 and C4A*6, and the C4B*2 B*92 duplication were only found in the Xhosa. C4A alleles A*4, A*45, A*58, A*12, A*14, A*19 and the C4A*3 A*91 duplication were only found in the San/Khoi population group. In the San, fourteen extended haplotypes were found in a relatively high frequency (2-7%). In the Xhosa, one extended haplotype (B42, C4A*12 A*91, C4B*Q0, DR18) was found in a very high frequency (13%) and was characteristic for this group; five other extended haplotypes were found with a low frequency (< 3%).

Complement C4a↗
PubMed1993

The value of variable number of tandem-repeat polymorphisms in cases of disputed paternity not resolved by conventional markers: two case reports.

Disputed paternity cases are routinely tested in the authors' laboratory for red cell antigen, plasma protein, red cell enzyme, and HLA polymorphisms. This report concerns two cases in which the above test results made exclusion of paternity doubtful. In one case, exclusion of paternity was based on one discrepancy in the Duffy blood group system only, a unique situation in the investigators' experience of more than 2500 cases; the investigators were, therefore, reluctant to use this as the only evidence of exclusion. In the other case, it was necessary to postulate the presence of a rare haplotype, MSu, in the MNS blood group system to explain paternity. It was therefore decided to investigate allelic variable number of tandem-repeat (VNTR) DNA polymorphisms in these disputed paternity trios. VNTR DNA typing convincingly excluded these accused men from paternity.

Blood Group Antigens↗
PubMed1993

Structural diversity in the HLA-A10 family of alleles: correlations with serology.

The HLA-A10 crossreacting group consists of the A25, A26, A34, A43 and A66 antigens. Here, we report allelic sequences for A43 and for 2 subtypes of both A26 and A34. Combining these results with previously determined sequences for A25, A26 and A66 enables molecular comparison of all the serologically defined A10 antigens. They form a closely related and well-defined group of alleles which may have originated with A*2601. Patterns of serological crossreactivity are correlated with sequence and a public epitope shared by A33 and members of the A10 family is localized to residues R62 and N63. The A*2501, A*4301 and A*6601 alleles appear to have derived from A*2601 by single gene conversion events with other HLA-A alleles. In the case of A*4301, the donor allele was probably an A29 allele as A*4301 has a small element of sequence in the alpha 1 helix (residues L62 and Q63) uniquely shared with A29. The chimaeric structure of A43 explains the reactivity of A43 molecules with both A10 and A29 alloantisera. The rare Oriental variant of A26 (A26v*) is encoded by an allele (A*2602) that differs from A*2601 by a unique nucleotide substitution which changes aspartate to asparagine at position 116 in the floor of the peptide binding groove. Thus A*2602 is a functionally distinct allele that originated by a point mutation. Alleles encoding A34 and A66 antigens are found to have very similar structures, explaining the difficulty in their serological definition.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1993

Combinatorial diversity in DR2 haplotypes.

Sequence analysis has identified multiple alleles at two loci that encode for the DR2 specificity. The loci, DRB1 and DRB5, are in linkage disequilibrium which can extend to alleles of the DQ loci. Serologic, cellular, and sequence-specific oligonucleotide probe (SSOP) typing techniques have been used to identify the DR2 haplotypes. In this report, we have characterized by SSOP typing and cDNA/DNA sequence analyses the combinatorial diversity of DR2 haplotypes. Cells were selected on the basis of unique serologic reactivity, unique associations of alleles of DR and DQ loci, and/or presence in populations which have not been extensively characterized for HLA diversity. An asymmetric polymerase chain reaction (PCR) amplification was applied to rapidly screen unique cells and to characterize DNA sequence in conjunction with more conventional cDNA sequence analysis. The sequence data confirm the lack of a DRB5 locus in the DR2"LUM" specificity, the unexpected association of DRB1*1602 and DRB5*010 alleles in a nonCaucasoid population, and the association of the allele DRB1*1503 with DRB5*0101 in black African, African American and native American individuals. The DRB1*1503 and DRB5*0101 alleles were identified in an unusual haplotype, DR2,DQ2. The combinatorial diversity of the DR2 haplotypes is extended by these studies in nonCaucasoid populations.

Alleles↗
PubMed1992

Distinctive HLA-A,B antigens of black populations formed by interallelic conversion.

Alleles encoding five HLA-A and B Ag characteristic of black populations have been isolated and their nucleotide sequences determined. In each case, the "black" allele is similar to a "related" allele found in caucasoid populations. The primary differences between these pairs of alleles are localized clusters of nucleotide substitutions that change two to five residues of the Ag recognition site. The pattern of differences indicates that the pairs of black and caucasoid alleles diverged primarily as a result of interallelic conversion events.

Africa↗
PubMed1992

Adult onset spinocerebellar ataxia linked to HLA in a South African kindred of mixed ancestry.

Hereditary spinocerebellar ataxia (SCA) is a relatively common disorder in the Western Cape region of South Africa. At present there are no genetic markers available for prenatal or presymptomatic diagnosis. A large kindred of mixed ancestry with late onset SCA was studied in which the disorder segregated in an autosomal dominant fashion. HLA typing was undertaken on 44 family members, and the HLA haplotypes were assigned on the basis of segregation. The LIPED computer program, with a correction factor allowing for the age of onset, was used to analyze the pedigree for linkage to HLA. Of 22 individuals in whom disease status could be definitely assessed, only one recombinant between HLA and the SCA locus occurred. The lod score reached a maximum of 4.13 at a recombination fraction of 0.05, indicating the odds to be approximately 13,500 to 1 in favor of linkage between HLA and the putative disease allele for SCA. A possible recombination within the HLA region suggested that the disease allele lies telomeric of the HLA region. In view of the recent demonstration of tight linkage between SCA1 and D6S89, however, HLA should not be used for presymptomatic diagnosis or genetic counselling.

Adolescent↗
PubMed1991

HLA DQ beta restriction fragment length polymorphism and rheumatoid arthritis. Association between DQw7 and rheumatoid arthritis in DR4-positive subjects.

Two variants of the HLA-DR4-linked DQw3 allele, namely DQw7 and DQw8, were analysed in patients of mixed ancestry (Cape Coloureds) with rheumatoid arthritis and in healthy individuals from the same population group using a DQ beta-specific cDNA probe. The DQw7 allele, identified by 3,4 kb Hind III or 3,7 kb and 6,9 kb Bam HI DQ beta-specific restriction fragments, was expressed in 93% of DR4-positive patients (N = 15), compared with 12.5% DR4-positive normal individuals (N = 8). This DQ variant showed a highly significant association (relative risk = 98; P less than 0.0001) with rheumatoid arthritis in this population group and may play a role in their susceptibility to this disease.

Alleles↗
PubMed1991

Unusual HLA-DR,DQ haplotypes found in South African families of black, Asian Indian, and mixed ancestral origin.

Four non-Caucasoid families with the unusual HLA-DR,DQ haplotypes DRw17,DQw7; DR9,DQw2; DR4,DQw2; and DR4,DQw5 were studied. All four haplotypes showed identical serological patterns to those seen with the equivalent Caucasoid antigens, but no HLA-Dw specificities could be assigned. TaqI restriction fragment length polymorphism (RFLP) patterns observed using DRB, DQB, and DQA probes showed that the DRw17,DQw7 haplotype may have originated from a homologous crossover between a DRw17,DQw2 haplotype and a haplotype with DQw7. The results obtained for the DR9,DQw2 and DR4,DQw2 haplotypes suggest that these could have resulted from recombination events with an ancestral "black" DQw2 haplotype. From the RFLP data, it is difficult to postulate the origin of the DR4,DQw5 haplotype being from a single recombination event.

Asian People↗
PubMed1990

The HLA genetic constitution of the Bushmen (San).

The HLA-A, -B, and -C antigens of 290 and the DR antigens of 212 !Kung San individuals were characterized. The most frequent antigens were HLA-A30 [gene frequency (gf) = 0.193], Bw58 (gf = 0.303), Cw6 (gf = 0.327), DR4 (gf = 0.273), and DQw3 (gf = 0.553). An unexpected finding was the low frequency of the classic African black antigen Bw42 (gf = 0.004). Marked differences as well as similarities in HLA gene frequencies were observed between the San and the South African Negroes, supporting the view that they had a common origin and were then separated for a very long time. During this period differences developed as a result of selective advantage in the Negroes following the pastoralist-agriculturalist way of life as opposed to the hunter-gatherer way of life. The picture is further complicated by the fact that gene flow, mostly from the San to the southern African Negroes, took place when they met again a few hundred years ago. The data also illustrate HLA haplotypes, linkage disequilibria, and four-locus haplotypes not previously seen in other human populations. The most frequent four-locus haplotype in the San, HLA-Aw43,Cw7,B7,DRw6 was also different from A30, Cw2,Bw42,DR3, the most common among the South African Negroes.

Africa, Southern↗
PubMed1990

Polymorphism of DRw52 and its association with DRw11 and DRw12 in South African blacks (Negroes) and individuals of mixed ancestry (Cape coloreds).

The HLA-DRB3 gene, which encodes the supertypic HLA-DRw52 antigen, has been shown to have limited polymorphism. The alleles at this locus are also in linkage disequilibrium with the alleles at the DRB1 locus. We have studied 16 DRw11 and three DRw12 haplotypes in the South African populations. Five of the DRw11,DQw7 haplotypes were associated with a TaqI restriction fragment length polymorphism which has not been previously described and which correlated with the DRB3 gene. This new variant, which has been called DRw52d, is confined to individuals of black or mixed ancestry. Two of the DRw11,DQw7 haplotypes were also associated with DRw52a or DRw52c and not with DRw52b as has always been observed in white populations. The less common DRw11,DQw6 haplotype, observed in four individuals, also revealed different allelic associations with the DRB3 gene, together with an unusual DQA association. None of the three DRw12,DQw7 haplotypes had the usual association with the DRw52b allele and also demonstrated two distinct DQA associations. The pattern of linkage disequilibrium of the HLA-D region loci in the South African black populations is more complex than in other populations. These findings may be of significance for the matching of unrelated donors for organ transplantation, as well as the study of disease association with HLA.

Alleles↗
PubMed1990

New HLA-DR2-related specificities detected in South African blacks and individuals of mixed ancestry.

This study describes a new HLA-DR2-related specificity DR2LUM (CT) present in South African Blacks and individuals of mixed ancestry (Cape Coloureds). It can be distinguished from the "classic" DR2 specificities. DRw15 and DRw16, using serological and Southern blot techniques. Although no HLA-Dw specificity could be assigned to the DR2LUM(CT) cells, borderline typing reactions with Dw2 HTCs were observed. Southern blot analysis using a DRB probe and the TaqI enzyme has shown that DR2LUM(CT) shared a 1.6 kb fragment with DRw15 and a 4.7 kb fragment with DR1 and DRw10, indicating sequence homology between DR2LUM(CT) and these alleles. In addition, another unusual HLA-DR2 haplotype was found. The DR antigen was typed serologically as DRw16 but showed a combination of restriction fragments which are associated with both the DRw15 and DRw16 specificities. This study demonstrates the value of investigating non-Caucasoid populations in further characterizing the polymorphisms of the HLA class II genes.

Autoradiography↗
PubMed1990

HLA frequencies in black Zimbabweans.

One-hundred-and-nineteen normal Black Zimbabweans were typed for HLA antigens. We found a close similarity between the HLA antigen frequencies in Zimbabweans and Black South Africans (Xhosa), another Bantu-speaking group. The only significant differences noted were for HLA-Aw36, -Bw53, -Cw6, -DR4 and -DQw3 (p less than 0.01). The most common HLA haplotypes in significant positive linkage disequilibrium in the two groups were different. The differences that were noted may be due to gene flow from the San to the Black South Africans, since it is thought that the Zimbabweans had little if any contact with the San.

Black People↗
PubMed1990

The association between HLA and rheumatoid arthritis in Zimbabwean blacks.

HLA-A, B, C, DR and DQ typing was done on 26 black Zimbabweans with rheumatoid arthritis and the respective antigen frequencies were compared with those in a group of 119 normal individuals from the same ethnic background. Only the DR4 antigen was significantly increased in frequency in the patients, confirming the association with this disease seen in other Black African populations.

Arthritis, Rheumatoid↗