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Biomedical subjects

C L Scholtz

Publications and source records attributed to C L Scholtz.

At least 19 recordsLinked to original sources
PubMed2003

Allelic variation in the promoter region of the LDL receptor gene: analysis of an African-specific variant in the FP2 cis-acting regulatory element.

DNA samples of 2303 individuals from nine different population groups were screened for variant -175g-->t in the promoter region of the low-density lipoprotein receptor (LDLR) gene. The -175g-->t variant detected at carrier frequencies of 3-10% in different African population groups was absent in the Caucasian and Asian (Chinese) individuals studied. In contrast to previous findings in Black South Africans where this polymorphism predominated in patients with familial hypercholesterolaemia (FH), it occurred at a significantly lower frequency in hypercholesterolaemics from the recently admixed Coloured population of South Africa compared with population-matched controls (P<0.0001). Haplotype and mutation analysis excluded the likelihood that this finding is due to association with a specific disease-related mutation in FH patients, although reversal of the positive association with FH observed in the Black population may, at least in part, be due to admixture linkage disequilibrium. Transient transfection studies in HepG2 cells demonstrated that the -175t allele is associated with a non-significant decrease ( approximately 7%) of LDLR transcription in the absence of sterols. The data presented in this study raise the possibility that the -175g-->t polymorphism may have subtle effects that become clinically important within certain genetic and/or environmental contexts.

Alleles↗
PubMed2001

Combined heterozygosity for methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C is associated with abruptio placentae but not with intrauterine growth restriction.

OBJECTIVE: This study was undertaken to investigate the involvement of MTHFR gene mutations C677T and A1298C implicated in vascular disease, in patients with abruptio placentae and intrauterine growth restriction (IUGR). STUDY DESIGN: DNA was extracted from blood samples of 54 patients with placental vasculopathy (18 patients with abruptio placentae and 36 with IUGR) and 114 control patients and amplified by the polymerase chain reaction (PCR). The resulting fragments were subjected to restriction enzyme analysis and resolved by gel electrophoresis. RESULTS: A significant association could be demonstrated between mutation A1298C and both abruptio placentae and IUGR. Combined heterozygosity for mutations C677T and A1298C was detected in 22.2% of abruptio placentae cases. CONCLUSIONS: Combined heterozygosity for MTHFR mutations C677T and A1298C may represent a genetic marker for abruptio placentae.

Abruptio Placentae↗
PubMed2000

Predominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia.

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 intragenic LDLR 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.

Adolescent↗
PubMed2000

Lipoprotein(a) determination and risk of cardiovascular disease in South African patients with familial hypercholesterolaemia.

OBJECTIVE: A raised plasma level of lipoprotein(a) (Lp(a)) is an established genetic risk factor for coronary heart disease (CHD), particularly in patients with concomitant elevation of low-density lipoprotein (LDL) cholesterol. The current study focused on the comparison of two commercially available Lp(a) assay kits to determine whether differences observed in measured Lp(a) levels could be deemed negligible in CHD risk assessment in familial hypercholesterolaemic (FH) patients. DESIGN: To compare results obtained on duplicate plasma samples using two commercially available Lp(a) measuring kits, the immunoradiometric assay (RIA) and the enzyme-linked immunoabsorbent assay (ELISA). SETTING: Division of Human Genetics, Department of Obstetrics and Gynaecology, University of Stellenbosch, Tygerberg, South Africa and the Institute for Medical Biology and Human Genetics, University of Innsbruck, Austria. SUBJECTS: Plasma samples were obtained from 146 family members of 65 molecularly characterised South African FH families for comparative analysis. RESULTS: Using the RIA method, 34 samples (23%) considered to be in the normal range by the ELISA technique, were placed in the high-risk group (> 30 mg/dl). Only one sample, considered to have a normal Lp(a) level with the RIA method, was categorised by the ELISA technique as high risk. CONCLUSION: Our data demonstrate that measurements of Lp(a) using the RIA method (the only assay available in South Africa at the time of this study) differ significantly from those obtained by the reference ELISA technique, suggesting that misclassification could lead to inaccurate CHD risk assessment. This is an important consideration in Afrikaner FH families, where plasma levels of Lp(a) have been shown to be elevated significantly in FH patients compared with non-FH individuals.

Adult↗
PubMed2000

Familial adenomatous polyposis coli in South Africa--molecular basis and diagnosis.

OBJECTIVE: To determine the molecular basis and establish a routine molecular diagnostic service for familial adenomatous polyposis coli (FAP) families in South Africa. DESIGN: The coding region of the adenomatous polyposis coli (APC) gene in affected FAP kindreds was screened using heteroduplex analysis, single-strand conformation polymorphism analysis and the protein truncation test. SETTING: Department of Human Genetics, University of Stellenbosch, and the Cancer Research Campaign Laboratories, Department of Pathology, University of Edinburgh and Molecular Medicine Centre, Western General Hospital, Edinburgh, Scotland (academic visit of 6 months). SUBJECTS: FAP-affected individuals and at-risk family members in 28 apparently unrelated South African families. RESULTS: A total of nine different APC mutations was identified, allowing DNA-based diagnosis in 20 families. Three of these mutations have not been described previously in other populations. CONCLUSION: Pre-symptomatic diagnosis using direct mutation detection is cost-effective and surgical intervention has the potential to prevent cancer in at-risk individuals from FAP families.

Adenomatous Polyposis Coli↗
PubMed1999

Founder mutations in the LDL receptor gene contribute significantly to the familial hypercholesterolemia phenotype in the indigenous South African population of mixed ancestry.

The South African population harbors genes that are derived from varying degrees of admixture between indigenous groups and immigrants from Europe and the East. This study represents the first direct mutation-based attempt to determine the impact of admixture from other gene pools on the familial hypercholesterolemia (FH) phenotype in the recently founded Coloured population of South Africa, a people of mixed ancestry. A cohort of 236 apparently unrelated patients with clinical features of FH was screened for a common mutation causing familial defective apolipoprotein B-100 (FDB) and seven low-density lipoprotein receptor (LDLR) gene defects known to be relatively common in South Africans with FH. Six founder-type 'South African mutations' were responsible for FH in approximately 20% of the study population, while only 1 patient tested positive for the familial defective apolipoprotein B-100 mutation R3500Q. The detection of multiple founder-type LDLR gene mutations originating from European, Indian and Jewish populations provides direct genetic evidence that Caucasoid admixture contributes significantly to the apparently high prevalence of FH in South African patients of mixed ancestry. This study contributes to our knowledge of the biological history of this unique population and illustrates the potential consequences of recent admixture in populations with different disease risks.

Founder Effect↗
PubMed1999

Mutation -59c-->t in repeat 2 of the LDL receptor promoter: reduction in transcriptional activity and possible allelic interaction in a South African family with familial hypercholesterolaemia.

The low-density lipoprotein receptor (LDLR) plays a major role in cholesterol homeostasis. Mutations in the regulatory region of the LDLR gene, although rare, have been shown to alter transcriptional activity of the gene and can cause familial hypercholesterolaemia (FH). In this study, a transition (c-->t) was identified at nucleotide position -59 within repeat 2 of the LDLR promoter in a South African FH patient of mixed ancestry. By screening 17 family members of the index case for this promoter mutation, two additional single base changes (-124c-->t and-175g-->t) were identified, located at recently described cis- acting regulatory sequences of the LDLR promoter. Both the-59c-->t and the-124c-->t transitions were identified in the normocholesterolaemic son of the index patient. Reporter plasmids containing the normal and mutant promoter fragments were constructed by directional cloning. Transcription studies using a luciferase reporter system demonstrated that the-59c-->t mutation significantly reduces promoter activity in both the presence and absence of sterols ( approximately 40% of normal activity), while the-124c-->t variant increases transcription ( approximately 160%) of the LDLR gene. The intra-familial phenotypic variability observed amongst individuals with the-59c-->t mutation can probably be ascribed to allelic interaction, suggesting that variation in the LDLR promoter region may contribute significantly to the phenotypic expression of FH-related mutations in populations where these mutations prevail.

Adolescent↗
PubMed1998

A 3-basepair deletion in repeat 1 of the LDL receptor promoter reduces transcriptional activity in a South African Pedi.

We have examined a naturally occurring mutation in the promoter region of the low density lipoprotein receptor (LDLR) gene of a South African Black patient with a clinical diagnosis of familial hypercholesterolemia (FH). The mutation constitutes a 3-bp deletion at nucleotide position -92 (FH Pedi-2) in the distal Sp1 binding site in repeat 1 of the LDLR promoter. The patient carries a second mutant LDLR allele containing a 1-bp deletion in exon 2 (FH Pedi-1) that gives rise to a frameshift mutation. Consistent with low receptor activity previously observed in cultured fibroblasts from the patient (5-15%), the rate of LDL receptor synthesis was markedly reduced to less than 20% of normal. DNase I footprint analysis indicated that the -92 mutation abolished binding of Sp1 to repeat 1 in the LDLR promoter. Transcription studies in transfected cells using normal and mutant promoter fragments linked to a luciferase reporter gene demonstrated that the promoter fragment containing the -92 mutation had approximately 10% of normal promoter activity. These findings indicate that the distal Sp1 binding site is essential for maximal activity of the normal intact LDLR promoter.

Arteriosclerosis↗
PubMed1997

A double mutant LDL receptor allele in a cypriot family with heterozygous familial hypercholesterolemia.

Two novel mutations Q363X and D365E were identified in the low-density lipoprotein receptor gene in a Cypriot patient with heterozygous familial hypercholesterolemia. Restriction enzyme analysis of the index case and seven of her family members, by using AvaII and PvuII respectively, demonstrated that the two exon 8 mutations are transmitted in cis within the family. The disease phenotype is probably caused by the stop-363 mutation; this would result in a truncated protein that would probably be rapidly degraded in the extracellular space.

Adolescent↗
PubMed1992

The effect of the microphthalmia gene on pre-natal optic nerve development in the mouse.

The purpose of this study was to examine the effect of the microphthalmia gene on pre-natal optic nerve development in the mouse. Coronal serial sections of wild-type, heterozygote and homozygous microphthalmic embryonic optic nerves are examined throughout gestation. No obvious morphological abnormality was identified in the heterozygote. The microphthalmic optic stalk/nerve was larger than that of the wild-type and heterozygote and there was persistence of the optic stalk throughout gestation. This was due to a high mitotic rate and reduced cell death in the dorsal layer of the microphthalmic optic stalk as well as persistence of the optic ventricle throughout gestation. The latter was associated with persistence of intermediate-type junctions between the neuroepithelial cells lining the ventricle and failure of the cells on the dorsal aspect of the distal stalk to degenerate. Possible mechanisms for the disappearance of the optic ventricle in the normal optic stalk are suggested.

Animals↗
PubMed1992

Axonal injury in closed head injury by assault: a quantitative study.

Due to the controversy in the literature regarding the time course of axonal balloon formation in human material, we wished to determine if it was possible to diagnose axonal injury before the development of axonal balloonings. The hypothesis was that the presence of axonal swellings or axonal enlargements associated with a glial reaction could be used as a diagnostic aid in human axonal injury before 12 hours. The brains of eight individuals that survived for less than 48 hours following head injury, and also had evidence of axonal injury using the criteria of Vanezis et al. (1987), were systematically studied by looking at axonal swellings, axonal balloonings, reactive astrocytes, maximum diameter of axonal enlargements and density of axonal enlargements. Controls were eight selected cases without neurological disease. The variables studied were assessed in 25 fields from ten different areas of the brain, using silver stains and immunoperoxidase for glial fibrillary acidic protein (GFAP). Logarithms of one plus the count of each variable were taken from the raw data and these were analysed using percentile distribution and the median, the t-test, Mann-Whitney U test and the Wilcoxon signed rank test. We conclude that quantitation of axonal damage allows the detection of mild degrees of axonal injury that could be overlooked on routine examination, and that the criteria of axonal enlargements, rather than axonal balloonings, are indications of axonal damage, cannot be endorsed with the evidence provided.

Axons↗
PubMed1991

The glial reaction in closed head injuries.

The development of the glial reaction in human closed head injury has been investigated using morphometry and statistical analysis. The brains of eight individuals that survived less than 48 h following closed head injury were analysed using immunoperoxidase for glial fibrillary acidic protein (GFAP). Controls were eight patients without neurological disease. The density of reactive astrocytes was estimated in 25 fields in each of 10 different areas sampled bilaterally avoiding the subpial and subependymal zones, and the perivascular white matter. There was great variation between the zones within and between groups, and considerable variation between individuals. The raw data were expressed as logarithms averaged and analysed using the median and non-parametric statistics. The corpus callosum in the head injury group showed the highest densities of reactive astrocytes, particularly in the splenium which achieved statistical significance using the non-parametric tests. This pattern was not reproduced in the control group. Although there was overlap between the head injured and control individuals, the head injury group had relatively higher densities in all zones, and showed an overall increase in the density of reactive astrocytes. This achieved statistical significance in the corpus callosum, the occipital subcortical white matter, and the cerebellum. This study has shown that the glial reaction is often prominent in the corpus callosum irrespective of the presence of a primary lesion although the pattern varies from case to case.

Adult↗
PubMed1991

The prenatal development of the optic fissure in colobomatous microphthalmia.

The coloboma in the cinnamon mouse homozygous for the microphthalmia gene is caused when optic fissure closure, which normally occurs between the 11th and the 13th gestational day, does not occur. This study sought to determine the cause of this fusion failure, and to identify any foci of fusion that occur later in gestation. Microphthalmic fetuses from the 11th-20th gestational day were obtained by datemating cinnamon mice heterozygous for the microphthalmia gene. Coronal serial sections of the eyes were examined at light and electron microscopy. Initially, the fissure margins became apposed only in the posterior aspects of the eye. A failure of basement membrane disintegration at the fissure margins prevented fusion at the 12th and 13th days. On the 14th day, small foci of basement membrane disintegration were identified in the area of the developing optic disc. Although the fusion zone enlarged later in gestation, it was limited to the area of the optic disc and showed that the two retinal layers did not separate. This study has shown that abnormal growth and invagination lead to delayed apposition of the optic fissure margins. These features together with a failure of basement membrane disintegration appear to be the main factors involved in coloboma formation. It is suggested that the excessive number of outer-layer cells that are inverted into the fissure, as well as abnormal or reduced numbers of phagocytic cells, may affect the persistence of the basement membrane. Alternatively, a primary defect of the pigment epithelial cell may lead to the development of the hypercellular and nonpigmented outer layer associated with the lack of basement membrane disintegration and nonfusion in this mutant.

Animals↗
PubMed1988

Selective and asymmetric vulnerability of corticospinal and spinocerebellar tracts in motor neuron disease.

The spinal cords of 10 cases of motor neuron disease were compared with those of six age-matched controls using myelin and silver impregnation methods, and the Marchi reaction for myelin degradation products. These studies revealed striking asymmetry in involvement of the lateral and anterior corticospinal tracts, without concordance in the pattern of involvement of these crossed and uncrossed corticospinal pathways. In addition there was prominent involvement of the posterior and anterior spinocerebellar tracts, but less marked abnormality was seen in the reticulospinal pathways. These findings highlight the asymmetrical involvement of the upper and lower motor neuron components of the motor system that is a characteristic feature of the disease, and demonstrate that involvement of the spinocerebellar system is a frequent finding.

Anterior Horn Cells↗
PubMed1988

The effect of the gene for microphthalmia (mi) on the dorsal lateral geniculate nucleus of the cinnamon mouse.

The dystrophic retina of the cinnamon mouse homozygous for the gene for microphthalmia (mi/mi) has a population of large ganglion cells. Unilateral enucleation and examination of the dorsal lateral geniculate nucleus using the Fink-Heimer technique showed that, while there was continuing degeneration argyrophilia in the dorsal lateral geniculate nucleus secondary to the retinopathy, there was additional degeneration attributable to enucleation. In addition, the pattern of degeneration indicated that the axon terminals were less mature than those of the cinnamon and heterozygous (mi/+) mice. Quantitative study of the dorsal lateral geniculate nucleus in the homozygous (mi/mi) mouse showed that the nucleus is small with fewer neurons and that the markers for protein metabolism, namely volume of nucleoli and cytoplasmic RNA, are reduced when compared to the cinnamon and heterozygous (mi/+) mice. It is concluded that the portion of the retino-geniculate pathway represented by the large ganglion cells in the retina, develops in the absence of patterned visual stimuli, but is less mature and has a more limited functional activity than controls.

Aging↗
PubMed1987

White matter damage following acute head injury.

The study of a series of brains from patients who had a severe head injury and died within 72 h without a lucid interval showed that there was a step-wise progression in the development of retraction balls. At 2 h after injury sinusoidal enlargement of the axons was evident. This progressed over 16 h when the lesions appeared as retraction balls which were fully developed at 72 h. There was a similar increase of staining with an immunoperoxidase method for glial fibrillary acid protein (GFAP) initially around blood vessels spreading diffusely into the white matter. The number of reactive astrocytes also increased. In a control case where the corpus callosum was torn at post-mortem there were sinusoidally distended and torn axons in the absence of GFAP staining. It is proposed that there are three components to a head injury. First, mechanical injury as seen in the control case; second, the development of retraction balls which are an active process probably representing damaged axons which cannot undergo repair where the sinusoidal swellings develop into retraction balls and third, an astrocytic reaction. The sinusoidal change, when present on its own, may not be separable from post-mortem trauma. However, when it is associated with an astrocytic response it should be correlated with coma in the same way as retraction balls.

Axons↗