35 research outputs found
Alcohol exposure during pregnancy altered childhood developmental trajectories in a rural South African community
Osteogenesis imperfecta type 3 in South Africa: Causative mutations in FKBP10
Background. A relatively high frequency of autosomal recessively inherited osteogenesis imperfecta (OI) type 3 (OI-3) is present in the indigenous black southern African population. Affected persons may be severely handicapped as a result of frequent fractures, progressive deformity of the tubular bones and spinal malalignment.Objective. To delineate the molecular basis for the condition.Methods. Molecular investigations were performed on 91 affected persons from seven diverse ethnolinguistic groups in this population.Results. Following polymerase chain reaction amplification and direct cycle sequencing, FKBP10 mutations were identified in 45.1% (41/91) OI-3-affected persons. The homozygous FKBP10 c.831dupC frameshift mutation was confirmed in 35 affected individuals in the study cohort. Haplotype analysis suggests that this mutation is identical among these OI-3-affected persons by descent, thereby confirming that they had a common ancestor. Compound heterozygosity of this founder mutation was observed, in combination with three different deleterious FKBP10 mutations, in six additional persons in the cohort. Four of these individuals had the c.831delC mutation.Conclusion. The burden of the disorder, both in frequency and severity, warrants the establishment of a dedicated service for molecular diagnostic confirmation and genetic management of persons and families with OI in southern Africa
Cytokine and Chemokine Concentrations as Biomarkers of Feline Mycobacteriosis
Abstract Mycobacteriosis is an emerging zoonotic disease of domestic cats and timely, accurate diagnosis is currently challenging. To identify differential cytokine/chemokine concentrations in serum/plasma of cats, which could be diagnostic biomarkers of infection we analysed plasma/serum from 116 mycobacteria-infected cats, 16 healthy controls and six cats hospitalised for unrelated reasons was analysed using the Milliplex MAP Feline Cytokine Magnetic Bead multiplex assay. Three cytokines; sFAS, IL-13 and IL-4 were reduced while seven; GM-CSF, IL-2, PDGF-BB, IL-8, KC, RANTES and TNF-α were elevated in mycobacteria-infected cats compared to healthy controls. However, IL-8 and KC concentrations were not significantly different from cats hospitalised for other reasons. Elevations in TNF-α and PDGF-BB may have potential to identify M. bovis and M. microti infected cats specifically while GM-CSF, IL-2 and FLT3L were increased in MTBC infected cats. This study demonstrates potential use of feline tuberculosis as a spontaneously occurring model of this significant human disease. Cytokine profiling has clear diagnostic potential for mycobacteriosis of cats and could be used discriminate tuberculous from non-tuberculous disease to rapidly inform on zoonotic risk. Future work should focus on the in-field utility of these findings to establish diagnostic sensitivity and specificity of these markers
Molecular Investigation of Familial Beckwith-Wiedemann Syndrome: A Model for Paternal Imprinting
Reduced DNA methylation at the PEG3 DMR and KvDMR1 loci in children exposed to alcohol in utero : a South African Fetal Alcohol Syndrome cohort study
CITATION: Masemola, M. L. 2015. Reduced DNA methylation at the PEG3 DMR and KvDMR1 loci in children exposed to alcohol in utero : a South African Fetal Alcohol Syndrome cohort study. Frontiers in Genetics, 6:85, doi: 10.3389/fgene.2015.00085.The original publication is available at http://journal.frontiersin.org/journal/geneticsFetal alcohol syndrome (FAS) is a devastating developmental disorder resulting from
alcohol exposure during fetal development. It is a considerable public health problem
worldwide and is characterized by central nervous system abnormalities, dysmorphic facial
features, and growth retardation. Imprinted genes are known to play an important role in
growth and development and therefore four imprinting control regions (ICRs), H19 ICR,
IG-DMR, KvDMR1 and PEG3 DMR were examined. It is proposed that DNA methylation
changes may contribute to developmental abnormalities seen in FAS and which persist
into adulthood. The participants included FAS children and controls from the Western
and Northern Cape Provinces. DNA samples extracted from blood and buccal cells were
bisulfite modified, the ICRs were amplified by PCR and pyrosequencing was used to derive
a quantitative estimate of methylation at selected CpG dinucleotides: H19 ICR (six CpG
sites; 50 controls and 73 cases); KvDMR1 (7, 55, and 86); IG-DMR (10, 56, and 84); and
PEG3 DMR (7, 50, and 79). The most profound effects of alcohol exposure are on neuronal
development. In this study we report on epigenetic effects observed in blood which may
not directly reflect tissue-specific alterations in the developing brain. After adjusting for
age and sex (known confounders for DNA methylation), there was a significant difference
at KvDMR1 and PEG3 DMR, but not the H19 ICR, with only a small effect (0.84% lower
in cases; p D 0.035) at IG-DMR. The two maternally imprinted loci, KvDMR1 and PEG3
DMR, showed lower average locus-wide methylation in the FAS cases (1.49%; p < 0.001
and 7.09%; p < 0.001, respectively). The largest effect was at the PEG3 DMR though the
functional impact is uncertain. This study supports the role of epigenetic modulation as
a mechanism for the teratogenic effects of alcohol by altering the methylation profiles of
imprinted loci in a locus-specific manner.http://journal.frontiersin.org/article/10.3389/fgene.2015.00085/fullPublisher's versio
Universal prevention is associated with lower prevalence of fetal alcohol spectrum disorders in Northern Cape, South Africa: a multicentre before-after study
Prevalence of fetal alcohol spectrum disorders (FASDs) is remarkably high in several provinces of South Africa; yet population-level knowledge of the harms of maternal drinking remains low. In two heavily affected areas, we assessed effectiveness of interventions to heighten awareness of these harms and to alter social norms about drinking in pregnancy.
FASD prevalence, maternal knowledge and drinking behaviours were investigated in two Northern Cape Province towns, before and after interventions which included highlighting FASD using local media and health promotion talks at health facilities. Independently, two dysmorphologists and a neuropsychometrist examined children at 9 and 18 months.
Pre-intervention maternal knowledge of alcohol harms was low and FASD prevalence 8.9% (72/809). Interventions reached high coverage and knowledge levels increased substantially. FASD prevalence was 5.7% post-intervention (43/751; P = 0.02); 0.73 lower odds, controlling for maternal age and ethnicity (95% confidence interval = 0.58-0.90). No change was detected in more severe FASD forms, but in the whole population, median dysmorphology scores reduced from 4 [inter-quartile range (IQR) = 2-7] to 3 (IQR = 1-6; P = 0.002).
This, the first prevention study using FASD outcomes, suggests that universal prevention might reduce FASD by similar to 30% and have population-level effects. This supports intensifying universal interventions where knowledge of harms of maternal drinking is low. These efforts need to be accompanied by alcohol-dependence treatment to lower more severe FASD forms