Publications by authors named "Nadia Carstens"

6 Publications

  • Page 1 of 1

Ending a diagnostic odyssey-The first case of Takenouchi-Kosaki syndrome in an African patient.

Clin Case Rep 2021 Apr 2;9(4):2144-2148. Epub 2021 Mar 2.

Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences University of the Witwatersrand Johannesburg South Africa.

First reported case of Takenouchi-Kosaki syndrome in an African patient with a likely pathogenic missense variant identified in the gene.
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April 2021

Familial congenital cataract, coloboma, and nystagmus phenotype with variable expression caused by mutation in in a South African family.

Mol Vis 2018 9;24:407-413. Epub 2018 Jun 9.

Division of Ophthalmology, Department of Neurosciences, University of Witwatersrand, Johannesburg, South Africa.

Purpose: To report on a clinical and genetic investigation of a large, multigenerational South African family of mixed ancestry with autosomal dominant congenital cataracts, coloboma, and nystagmus.

Methods: Ophthalmic examination was performed in 27 individuals from the same admixed South African family. DNA was sampled from either peripheral blood or buccal swabs in all 27 individuals, and whole genome sequencing was performed in six individuals. Sanger sequencing was used to validate the probable mutation in the remaining family members.

Results: Twenty-seven family members with 19 affected individuals were included in the study. The predominant phenotype, with highly variable expression, was congenital cataract (14 individuals), posterior segment coloboma (17 individuals), and nystagmus (18 individuals). Other features present included high myopia, microcornea, and strabismus. An R208W mutation in (dbSNP rs757259413; HGMD CM930572; NM_000280.3:c.622G>A; NP_000271.1:p.Arg208Trp) was identified as being the most probable pathogenic mutation. Cosegregation of the mutation with the phenotype was confirmed in all 27 family members.

Conclusions: is a highly conserved gene crucial for normal oculogenesis, and although mutations within the gene may cause an array of ocular developmental abnormalities, most are associated with aniridia and aniridia-related ocular defects. The observation that aniridia phenotypes are largely associated with nonsense mutations and milder non-aniridia phenotypes with missense mutations suggested that there may be specific genotype-phenotype correlations for the gene. The R208W mutation in identified in this family challenges this theory as it has previously been reported in three unrelated families and is associated with aniridia and non-aniridia phenotypes across the four families. with its wide phenotypic associations and highly variable expression should be considered a candidate gene in the diagnostic screen for any ocular developmental abnormality.
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November 2018

Organic Cation Transporter 2 (OCT2/SLC22A2) Gene Variation in the South African Bantu-Speaking Population and Functional Promoter Variants.

OMICS 2017 03 16;21(3):169-176. Epub 2017 Feb 16.

1 The School of Molecular and Cell Biology, University of the Witwatersrand , Johannesburg, South Africa .

SLC22A2 facilitates the transport of endogenous and exogenous cationic compounds. Many pharmacologically significant compounds are transported by SLC22A2, including the antidiabetic drug metformin, anticancer agent cisplatin, and antiretroviral lamivudine. Genetic polymorphisms in SLC22A2 can modify the pharmacokinetic profiles of such important medicines and could therefore prove useful as precision medicine biomarkers. Since the frequency of SLC22A2 polymorphisms varies among different ethnic populations, we evaluated these in South African Bantu speakers, a majority group in the South African population, who exhibit unique genetic diversity, and we subsequently functionally characterized promoter polymorphisms. We identified 11 polymorphisms within the promoter and 9 single-nucleotide polymorphisms (SNPs) within the coding region of SLC22A2. While some polymorphisms appeared with minor allele frequencies similar to other African and non-African populations, some differed considerably; this was especially notable for three missense polymorphisms. In addition, we functionally characterized two promoter polymorphisms; rs138765638, a three base-pair deletion that bioinformatics analysis suggested could alter c-Ets-1/2, Elk1, and/or STAT4 binding, and rs59695691, an SNP that could abolish TFII-I binding. Significantly higher luciferase reporter gene expression was found for rs138765638 (increase of 37%; p = 0.001) and significantly lower expression for rs59695691 (decrease of 25%; p = 0.038), in comparison to the wild-type control. These observations highlight the importance of identifying and functionally characterizing genetic variation in genes of pharmacological significance. Finally, our data for SLC22A2 attest to the importance of considering genetic variation in different populations for drug safety, response, and global pharmacogenomics, through, for example, projects such as the Human Heredity and Health in Africa initiative.
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March 2017

Novel mutation in the CHST6 gene causes macular corneal dystrophy in a black South African family.

BMC Med Genet 2016 07 20;17(1):47. Epub 2016 Jul 20.

Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, 2050, Johannesburg, Gauteng, South Africa.

Background: Macular corneal dystrophy (MCD) is a rare autosomal recessive disorder that is characterized by progressive corneal opacity that starts in early childhood and ultimately progresses to blindness in early adulthood. The aim of this study was to identify the cause of MCD in a black South African family with two affected sisters.

Methods: A multigenerational South African Sotho-speaking family with type I MCD was studied using whole exome sequencing. Variant filtering to identify the MCD-causal mutation included the disease inheritance pattern, variant minor allele frequency and potential functional impact.

Results: Ophthalmologic evaluation of the cases revealed a typical MCD phenotype and none of the other family members were affected. An average of 127 713 variants per individual was identified following exome sequencing and approximately 1.2 % were not present in any of the investigated public databases. Variant filtering identified a homozygous E71Q mutation in CHST6, a known MCD-causing gene encoding corneal N-acetyl glucosamine-6-O-sulfotransferase. This E71Q mutation results in a non-conservative amino acid change in a highly conserved functional domain of the human CHST6 that is essential for enzyme activity.

Conclusion: We identified a novel E71Q mutation in CHST6 as the MCD-causal mutation in a black South African family with type I MCD. This is the first description of MCD in a black Sub-Saharan African family and therefore contributes valuable insights into the genetic aetiology of this disease, while improving genetic counselling for this and potentially other MCD families.
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July 2016

Genetic variation in angiotensin II type 2 receptor gene influences extent of left ventricular hypertrophy in hypertrophic cardiomyopathy independent of blood pressure.

J Renin Angiotensin Aldosterone Syst 2011 Sep 16;12(3):274-80. Epub 2010 Dec 16.

MRC Centre for Molecular and Cellular Biology, Department of Biomedical Sciences, University of Stellenbosch Health Sciences Faculty, Tygerberg, South Africa.

Introduction: Hypertrophic cardiomyopathy (HCM), an inherited primary cardiac disorder mostly caused by defective sarcomeric proteins, serves as a model to investigate left ventricular hypertrophy (LVH). HCM manifests extreme variability in the degree and distribution of LVH, even in patients with the same causal mutation. Genes coding for renin-angiotensin-aldosterone system components have been studied as hypertrophy modifiers in HCM, with emphasis on the angiotensin (Ang) II type 1 receptor (AT(1)R). However, Ang II binding to Ang II type 2 receptors (AT(2)R) also has hypertrophy-modulating effects.

Methods: We investigated the effect of the functional +1675 G/A polymorphism (rs1403543) and additional single nucleotide polymorphisms in the 3' untranslated region of the AT(2)R gene (AGTR2) on a heritable composite hypertrophy score in an HCM family cohort in which HCM founder mutations segregate.

Results: We find significant association between rs1403543 and hypertrophy, with each A allele decreasing the average wall thickness by ~0.5 mm, independent of the effects of the primary HCM causal mutation, blood pressure and other hypertrophy covariates (p = 0.020).

Conclusion: This study therefore confirms a hypertrophy-modulating effect for AT(2)R also in HCM and implies that +1675 G/A could potentially be used in a panel of markers that profile a genetic predisposition to LVH in HCM.
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September 2011