Browsing by Author "De Villiers, J. N. P."

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    A multi-disciplinary approach towards elucidating the genetics of multiple sclerosis
    (Stellenbosch : Stellenbosch University, 2003-03) De Villiers, J. N. P.; Kotze, Maritha J.; Warnich, L.; De Jong, G.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics.
    ENGLISH ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Current knowledge suggests that MS is associated with autoimmunity and that infectious agents and hereditary factors may be involved. The demonstration of a higher recurrence risk of MS in families (4-5%) compared with the general population (0.1%) provides strong evidence for a genetic basis. Extensive analyses of the entire human genome to identify new genes that may underlie MS have indicated that several genes may contribute to disease susceptibility, but these remain largely unidentified. In this study candidate genes involved in iron metabolism and immunology have been analysed for the first time within the context of both autoimmune and infectious disease susceptibility, in order to investigate the role of genetic and viral factors implicated in the pathogenesis of MS. The Z-DNA forming repeat polymorphism in the promoter region of the solute carrier family 11 (proton-coupled divalent ion transporters) member 1 (SLC11A1) gene was found to be significantly associated with MS (P<0.01) in the genetically homogeneous Afrikaner population of South Africa, but not in the German and French populations using a case-control study and transmission linkage disequilibrium approach, respectively. However, significant differences were observed in genotype distribution between German MS patients with a primary- and secondary progressive disease course (P<0.05), and between the German patients with relapsing remitting and primary progressive MS (P<0.05). These findings provide further evidence that the SLC11A1 gene is associated with MS, most likely due to its role in iron homeostasis. In order to investigate the influence of viruses in the apparent multi-step aetiology of MS, serum and peripheral blood mononuclear cells (PBMCs) of MS patients, close relatives and unrelated controls were screened for the presence of MS-associated retrovirus (MSRV) and two herpes virus (HHV-6 and EBV) sequences. Detection of the pol gene expression of MSRV in the serum RNA of 69% of South African MS patients and in 70% of their unaffected close relatives, whilst absent in the serum of 39 unrelated healthy control individuals (P<0.001), indicated that virus infections affect the population risk but not the familial risk in MS. HHV-6 sequences were also present at a significantly lower frequency (P<0.04) in the PBMCs of unrelated controls (5%) compared to MS patients (22.5%). A point mutation (77C^G) in the gene encoding protein-tyrosine phosphatase, receptortype C (PTPRC), which is essential for activation of T and B cells, was found to be associated with MS in the German population. Analysis of the Afrikaner and German study populations included in our study did not indicate a causative role for the PTPRC gene in MS. However, it seems likely that this mutation may contribute to disease expression, since in one of the South African families with two MS affected sibs, the most severely affected sister was heterozygous for the 77C-»G mutation. The PTPRC mutation may therefore be of significance in disease prognosis. The multidisciplinary study approach has led to a stepwise accumulation of scientific information, which forever changed our understanding of the disease process underlying MS.
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    Predominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia
    (BMJ Publishing Group Ltd., 2000-02) Thiart, R.; Scholtz, C. L.; Vergotine, J.; Hoogendijk, C. F.; De Villiers, J. N. P.; Nissen, H.; Brusgaard, K.; Gaffney, D.; Hoffs, M. S.; Vermaak, W. J.; Kotze, M. J.
    In South Africa, the high prevalence of familial hypercholesterolaemia (FH) among Afrikaners, Jews, and Indians as a result of founder genes is in striking contrast to its reported virtual absence in the black population in general. In this study, the molecular basis of primary hypercholesterolaemia was studied in 16 Africans diagnosed with FH. DNA analysis using three screening methods resulted in the identification of seven different mutations in the coding region of the low density lipoprotein (LDLR) gene in 10 of the patients analysed. These included a 6 bp deletion (GCGATG) accounting for 28% of defective alleles, and six point mutations (D151H, R232W, R385Q, E387K, P678L, and R793Q) detected in single families. The Sotho patient with missense mutation R232W was also heterozygous for a de novo splicing defect 313+1G→A. Several silent mutations/polymorphisms were detected in the LDLR and apolipoprotein B genes, including a base change (g→t) at nucleotide position −175 in the FP2 LDLR regulatory element. This promoter variant was detected at a significantly higher (p<0.05) frequency in FH patients compared to controls and occurred in cis with mutation E387K in one family. Analysis of four intragenicLDLR gene polymorphisms showed that the same chromosomal background was identified at this locus in the four FH patients with the 6 bp deletion. Detection of the 6 bp deletion in Xhosa, Pedi, and Tswana FH patients suggests that it is an ancient mutation predating tribal separation approximately 3000 years ago.