SUNScholar - Browsing by Author "Kotze, M. J."

Browsing by Author "Kotze, M. J."

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Analysis of two mutations in the MTHFR gene associated with mild hyperhomocysteinaemia - heterogeneous distribution in the South African population
(Health & Medical Publishing Group, 2002-6) Scholtz, C. L.; Odendaal, H. J.; Thiart, R.; Loubser, L.; Hillermann, R.; Delport, R.; Hayward Vermaak, W. J.; Kotze, M. J.
Objective. The frequencies of mutations 677C→T and 1298A→C in the methylenetetrahydrofolate reductase (MTHFR) gene, previously shown to be associated with decreased enzyme activity that may lead to hyperhomocysteinaemia and consequently increased risk of cardiovascular disease (CVD), were determined in the South African population. Methods. HinfI (677C→T) and MboII (1298A→C) restriction enzyme analyses were performed on amplified DNA samples of 76 white, 73 coloured and 60 black subjects. Results. The mutant alleles of mutations 677C→T and 1298A→C were more common in the white (allele frequencies 0.36 and 0.37, respectively) than in the black population (0.04 and 0.09), while intermediate frequencies were detected in the coloured population (0.18 and 0.30). Homozygosity for mutation 677C→T was not detected in the black cohort, while this genotype was detected in 1 coloured (1.4%) and 8 white (10.5%) subjects. In the black population, 5% of the 60 subjects analysed were homozygous for mutation 1298A→C, compared with approximately 12% in both the white and coloured populations. Conclusions. Since hyperhomocysteinaemia is a risk factor for premature CVD, the heterogeneous distribution of the 677C→T and 1298A→C mutations across ethnic groups may partly explain ethnic differences in heart disease risk through decreased enzyme activity and hence increased homocysteine levels.
Application of advanced molecular technology in the diagnosis and management of genetic disorders in South Africa
(Health & Medical Publishing Group, 2016) Kotze, M. J.
Background. Genetic testing has evolved from a niche speciality for diagnosis of rare disorders and carrier screening to subtyping of complex medical conditions for targeted treatment. Genes causing monogenic disorders are well characterised, but risk management of multifactorial and polygenic disorders guided from the genetic background remains a challenge. Objective. This study describes the use of a pathology-supported genetic testing (PSGT) strategy designed to facilitate the move from single- to multi-gene testing and next-generation sequencing (NGS). Methods. In contrast to direct-to-consumer genetic testing, PSGT requires preselection of patients and data integration to determine current and future risk implications. To enable this process, a genomics database resource generated at the interface between the laboratory and clinic is available for clinical interpretation. Results. The PSGT approach led to the development of testing algorithms for improved clinical management of patients with cancer and other complex disorders with a genetic component. Local evidence is presented to demonstrate the application of PSGT for assessment of clinical relevance in patients with rare germline variants and functional polymorphisms underlying shared disease pathways. Conclusion. PSGT is ideally suited to serve as a screening step for microarray analysis and whole genome/exome sequencing as the next frontier in personalised medicine. Use of these advanced molecular technologies to match genotype with phenotype provides a resource for diagnosis and discovery over a lifetime.
Clinical versus molecular diagnosis of heterozygous familial hypercholesterolaemia in the diverse South African population
(Health & Medical Publishing Group, 2001) Vergotine, J.; Thiart, R.; Kotze, M. J.
Objective. Familial hypercholesterolaemia (FH) is a common genetic disease characterised by strikingly elevated plasma cholesterol concentration, which can lead to premature coronary death if left untreated. In this study DNA diagnosis of FH, which allows detection before onset of clinical symptoms, was evaluated against biochemical parameters routinely used to identify subjects with FH. Design. A population-based strategy was used to identify low-density lipoprotein receptor (LDLR) gene defects in South Africans with clinical signs of FH, followed by a family-based DNA screening approach for presymptomatic diagnosis of FH. Results. DNA screening of 790 at-risk relatives for the FH-related mutations identified in 379 index cases, allowed accurate disease diagnosis in an additional 338 relatives and exclusion of the relevant mutation in 452 individuals. The sensitivity and specificity of the diagnosis, based on total cholesterol values measured in family members of FH heterozygous index cases with one of the three founder-related mutations, D154N, D206E and V408M, were 89.3% and 81.9%, respectively. Conclusion. The predominance of 10 LDLR gene mutations in the local populations justifies population-directed DNA diagnosis of FH in South Africa on a routine basis, particularly since expression of the defective gene measured in biochemical tests does not allow accurate diagnosis of FH in all cases. DNA testing provides a definitive tool for family tracing aimed at pre-clinical diagnosis and preventive treatment of FH.
A DNA polymorphism in the human low-density lipoprotein receptor gene
(Health and Medical Publishing Group -- HMPG, 1986-07) Kotze, M. J.; Retief, A. E.; Brink, P. A.; Weich, H. F. H.
A new restriction fragment length polymorphism (RFLP) in the low-density lipoprotein receptor gene is described using the Stu I restriction endonuclease and a cDNA probe. The frequency of the two RFLP alleles was determined in 60 unrelated white subjects and 11,70/6 of them were found to be heterozygous for the polymorphism. Mendelian segregation of the RFLP was found in 3 informative families. The possible use of the RFLP in the diagnosis of familial nypercholesterolaemia in South Africa is discussed.
High specificity makes DNA screening the method of choice for diagnosis of familial hypercholesterolaemia
(Health & Medical Publishing Group, 2001) Kotze, M. J.
The diagnosis of familial hypercholesterolaemia (PH) is based on clinical findings, a family history of premature atherosclerosis and elevated plasma cholesterol levels.' Identification of heterozygous PH is complicated by the fact that biochemical parameters may overlap between normal and affected individuals, especially in children! and most adult patients do not present with cholesterol deposits in the skin and tendons. The importance of a DNA test that can provide a simple yes/no answer has now been demonstrated clearly in the article by Vergotine and colleagues in this issue of the Journal.
The identification of two low-density lipoprotein receptor gene mutations in South African familial hypercholesterolaemia
(Health & Medical Publishing Group, 1989) Kotze, M. J.; Langenhoven, E.; Warnich, Louise; Du Plessis, L.; Marx, M. P.; Oosthuizen, C. J. J.; Retief, A. E.
Two point mutations were discovered in the low-density lipoprotein genes of patients with familial hypercholesterolaemia (FH). Defective genes were cloned and/or amplified by the polymerase chain reaction (PCR) method and the DNA sequences determined. A guanine to adenine base transition in exon 4 was found to be the molecular defect in 20% of cases of FH in the Afrikaner population. A second mutation, a guanine to adenine base substitution in exon 9, was identified in two homozygous FH individuals. Restriction enzyme analysis of PCR-amplified DNA from blood and tissue samples now permits accurate diagnosis of these mutations.
Inherited colon cancers
(Health & Medical Publishing Group, 2000) Goldberg, P. A.; Madden, M. V.; Harocopos, C.; Grobbelaar, J. J.; Kotze, M. J.; Marx, M. P.; De Jong, G.
Grobbelaar et al.' and Ramesar et al.' (in this issue) have identified germline mutations in certain families with h"o different types of inherited colorectal cancers. This means that blood tests are now available in South Africa for clinical use in these particular families. Within the families these DNA-based tests can separate individuals with the mutation that causes cancer from those who do not have it. Those with a mutation may pass the family-specific mutation to their children.
Molecular characterisation of a low-frequency mutation in exon 8 of the human low-density lipoprotein receptor gene
(Health & Medical Publishing Group, 1989) Kotze, M. J.; Langenhoven, E.; Warnich, Louise; Marx, M. P.; Retief, A. E.
The prevalence of familial hypercholesterolaemia (FH), an autosomal dominant disease characterised by raised low-density lipoprotein (LDL) cholesterol levels, is at least five times higher in the white Afrikaner population than in most other population groups in the world. A founder gene effect has been suggested to explain this abnormally high frequency. Detection of a polymorphic Stu I site in the 5' region of the LDL receptor gene and association of both restriction fragment length polymorphism alleles with FH in Afrikaners, indicated the existence of at least two founder members of the disease in this population. DNA from a hetero-allelic FH homozygote from this South African group has been analysed through genomic cloning and sequencing. The DNA polymorphic site is caused by a single guanine to adenine transition within exon 8 of the LDL receptor gene and can be used in the determination of haplotype-associated defects.
Non-alcoholic fatty liver disease (NAFLD) in the Western Cape : a descriptive analysis
(Health and Medical Publishing Group (HMPG), 2010) Kruger, F. C.; Daniels, C.; Kidd, M.; Swart, G.; Brundyn, K.; Van Rensburg, C.; Kotze, M. J.
Background. Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in Western countries, but the disease profile has not yet been described in South Africa. NAFLD affects all spheres of society, especially the poorest and least educated. Aim. To investigate the demographics and clinical and biochemical features of South African patients diagnosed with non-alcoholic fatty liver and non-alcoholic steatohepatitis (NASH) in the Western Cape, South Africa. Design/method. Overweight/obese subjects were screened by ultrasound and those with fatty liver/hepatomegaly were included. Liver biochemistry, insulin resistance (using the insulin resistance homeostasis model assessment method for insulin resistance, HOMA-IR) and body mass index were assessed and liver biopsies were performed on patients older than 45 years with persistently abnormal liver function and/ or hepatomegaly. Results. We screened 233 patients: 69% coloured, 25% Caucasian, 5% black and 1% Asian. The majority (73%) were female. NAFLD was confirmed histologically in 111 patients, of whom 36% had NASH and 17% advanced liver fibrosis. No black patient had advanced fibrosis. Subjects with NASH had higher mean triglyceride (p=0.03) and cholesterol (p=0.01) levels than subjects with NAFL. All patients were insulin resistant/diabetic. HOMA-IR and not the degree of obesity was strongly associated with advanced fibrosis (p=0.09). Conclusion. This study is the first to describe the clinical characteristics of NAFLD in South Africa, albeit only in the Western Cape population. Insulin resistance was the universal factor present. The degree of obesity was not associated with severity of disease. The role of genetic risk factors in disease development and severity remains to be defined.
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.
Recurrent LDL-receptor mutation causes familial hypercholesterolaemia in South African coloureds and Afrikaners
(Health & Medical Publishing Group, 1995) Kotze, M. J.; Langenhoven, E.; Theart, L.; Loubser, O.; Micklem, A.; Oosthuizen, C. J. J.
Three low-density lipoprotein receptor (LDLR) gene mutations were previously shown to cause familial hypercholesterolaemia (FH) in up to 90% of affected Afrikaners. Association of each mutation with a single chromosomal background provided molecular genetic evidence that the proposed 'founder gene effect' was responsible for the high prevalence of FH among white Afrikaners. In this study we report the identification of the FH Afrikaner-2 (FH2) mutation, Val408 to Met, in the so-called coloured population of South Africa, a people of mixed ancestry, with rapid non-radioactive methods for mutation detection. Haplotype analysis with polymorphisms on both sides of the FH2 mutation indicated that the identical LDLR gene mutations found in two different South African population groups were caused by independent events at a potential CpG mutational 'hot spot'. The allelic variation giving rise to the different chromosomal backgrounds of the FH2 mutation does not affect the properties of the abnormal LDLR protein product which causes FH in these subjects. This mutation is thus expected to cause the same severe form of FH in affected coloureds as was previously demonstrated in Afrikaners. Detection of mutant LDLR gene alleles in polymerase chain reaction products, directly after gel electrophoresis, now allows accurate presymptomatic diagnosis of the FH2 mutation in FH patients from two different South African population groups.
The use of DNA markers in the pre-clinical diagnosis of familial adenomatous polyposis in families in South Africa
(Health & Medical Publishing Group, 1995) Grobbelaar, J. J.; Oosthuizen, C. J. J.; Madden, M. V.; Bailey, S. E.; Retief, A. E.; Kotze, M. J.
Haplotype association studies were performed in 10 unrelated South African families and 1 German immigrant family with familial adenomatous polyposis (FAP). Three DNA probes, recognising five restriction fragment length polymorphisms (RFLPs) around the gene locus for FAP on chromosome 5q, were used. The RFLP analysis was informative or partially informative in all the families studied. Five haplotypes were found to segregate with the disease locus. The predominant association of two of these haplotypes with FAP in the South African families suggests that two mutations may cause the disease in about 70% of families in this population. Meiotic recombination events were detected between the FAP gene and probe M4 (D5S6), but not probes Pi227 (D5S37) and C11p11 (D5S71). Haplotype analysis allowed the preclinical diagnosis of FAP in 5 subjects.

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