Autosomal recessive corneal hereditary endothelial dystrophy (CHED) is a rare congenital disorder of cornea. Mutations in SLC4A11 gene are associated with CHED phenotype. CHED is also an early feature of Harboyan syndrome. The aim of the present study was to identify genetic mutations in the SLC4A11 gene in CHED cases belonging to inbred Pakistani families. Furthermore, all homozygous mutation carriers were investigated for hearing deficit.
Methods and resultsThis study included consanguineous CHED families presented at Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan from June 2018 to September 2018. DNA was extracted from blood samples. Direct sequencing of SLC4A11 gene was performed. All identified variants were evaluated by in silico programs i.e., SIFT, PolyPhen‐2, and MutationTaster. Pathogenicity of the two identified splice site variants was analyzed by Human Splicing Finder and MaxEnt Scan. Screening of five CHED families revealed a total of three previously un reported (p.Arg128Gly, c.2241-2A?>?T and c.1898-2A?>?C in family CHED19, CHED22 and CHED26 respectively) and two already reported homozygous disease causing variants (p.Arg869Cys and p.Val824Met in family CHED24 and CHED25 respectively) as predicted by mutation taster. All of these variants segregated with disease phenotype and were not detected in controls.
ConclusionAffected individuals of the five CHED families screened in this study had the disease due to SLC4A11 mutations and progressing to Harboyan syndrome. Identification of previously unreported mutations aid to heterogeneity of SLC4A11 and CHED pathogenesis as well as helped to provide genetic counseling to affected families.
相似文献Background
The potential for emergence and spread of HIV drug resistance from rollout of antiretroviral (ARV) pre-exposure prophylaxis (PrEP) is an important public health concern. We investigated determinants of HIV drug resistance prevalence after PrEP implementation through mathematical modeling.Methodology
A model incorporating heterogeneity in age, gender, sexual activity, HIV infection status, stage of disease, PrEP coverage/discontinuation, and HIV drug susceptibility, was designed to simulate the impact of PrEP on HIV prevention and drug resistance in a sub-Saharan epidemic.Principal Findings
Analyses suggest that the prevalence of HIV drug resistance is influenced most by the extent and duration of inadvertent PrEP use in individuals already infected with HIV. Other key factors affecting drug resistance prevalence include the persistence time of transmitted resistance and the duration of inadvertent PrEP use in individuals who become infected on PrEP. From uncertainty analysis, the median overall prevalence of drug resistance at 10 years was predicted to be 9.2% (interquartile range 6.9%–12.2%). An optimistic scenario of 75% PrEP efficacy, 60% coverage of the susceptible population, and 5% inadvertent PrEP use predicts a rise in HIV drug resistance prevalence to only 2.5% after 10 years. By contrast, in a pessimistic scenario of 25% PrEP efficacy, 15% population coverage, and 25% inadvertent PrEP use, resistance prevalence increased to over 40%.Conclusions
Inadvertent PrEP use in previously-infected individuals is the major determinant of HIV drug resistance prevalence arising from PrEP. Both the rate and duration of inadvertent PrEP use are key factors. PrEP rollout programs should include routine monitoring of HIV infection status to limit the spread of drug resistance. 相似文献Heavy metal (HM) contamination of the environment is a serious threat to sustainable crop production. Among the HMs, chromium (Cr) is one of the most toxic HMs that is known to negatively affect growth and metabolic activities of diverse crop plants. The present study was designed to investigate the ameliorative role of 5-aminolevulinic acid (ALA) under Cr stress in two maize (Zea mays L.) cultivars showing differential sensitivity to Cr tolerance. ALA is a biosynthesis precursor and it has a dominant regulatory effect related to physiological, respiratory, and photosynthesis processes in various plant species. Three concentrations of Cr (0, 5, and 10 mg kg−1) were tested under the graded levels of ALA application (0, 12.5, and 25 mg L−1). The results indicated that Cr stress differentially reduced plant growth attributes, gas exchange characteristics, photosynthetic pigments, and biomass in both the cultivars. Oxidative stress increased as evidenced in the form of electrolyte leakage, malondialdehyde, and hydrogen peroxide (H2O2) accumulation in plants. The anti-oxidative enzyme activities, that is, catalase (CAT), superoxide dismutase (SOD), and peroxidase (POD) both in the leaves and roots of maize cultivars decreased due to Cr stress. The concentration of Cr increased in roots and shoots of maize under Cr levels without ALA. Under Cr stress, ALA exogenous application markedly enhanced plant growth, photosynthetic pigments, gas exchange capacity, and biomass. Furthermore, ALA application decreased the Cr-induced oxidative stress in maize cultivars by improving the activities of CAT, POD, and SOD in plants. After ALA application, the Cr concentrations and total Cr uptake by plants differently decreased in both cultivars. The 6103 cultivar of maize was found to be a tolerant cultivar against Cr stress due to its strong defensive system with a higher rate of antioxidant enzyme activities. On the other hand, the other maize cultivar (9108) was found to be a sensitive cultivar against Cr stress due to its weak defense system with higher contents of reactive oxygen species. These findings suggest that ALA can play a regulatory role in maintaining optimum plant growth and efficient photosynthetic processes under Cr-challenged habitats in maize. Thus, ALA application may be used as a sustainable remedial strategy to alleviate Cr-induced stress in maize cultivars.
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