Epidemiology of PAX6 Gene Pathogenic Variants and Expected Prevalence of PAX6-Associated Congenital Aniridia across the Russian Federation: A Nationwide Study
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SUBMITTER: Vasilyeva T
PROVIDER: S-EPMC10671545 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:Purpose:To investigate the association between PAX6 genotype and macular morphology in congenital aniridia. Methods:The study included 37 participants (15 males) with congenital aniridia (aged 10-72 years) and 58 age-matched normal controls (18 males). DNA was isolated from saliva samples. PAX6 exons, intron/exon junctions, and known regulatory regions were amplified in PCR and sequenced. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect larger deletions or duplications in PAX6 or known cis-regulatory regions. Spectral-domain optical coherence tomography images were acquired and segmented semiautomatically. Mean thicknesses were calculated for inner and outer retinal layers within the macula along nasal and temporal meridians. Results:Mutations in PAX6 or regulatory regions were found in 97% of the participants with aniridia. Foveal hypoplasia was observed in all who had a mutation within the PAX6 gene. Aniridic eyes had thinner outer retinal layers than controls, but with large between-individual variation (mean ± SD, 156.3 ± 32.3 µm vs 210.8 ± 12.3 µm, P < 0.001). Parafoveal and perifoveal inner and outer retinal layers were thinner in aniridia. Participants with mutations in noncoding PAX6 regions had thicker foveal outer retinal layers than those with mutations in the PAX6 coding regions (P = 0.04) and showed signs of postnatal development and maturation. Mutations outside the PAX6 gene were associated with the mildest retinal phenotypes. Conclusions:PAX6 mutations are associated with significant thinning of macular inner and outer retinal layers, consistent with misdirected retinal development resulting in abnormal foveal formation and reduced number of neurons in the macula, with mutations in PAX6 coding regions giving the worst outcome.
| S-EPMC7405610 | biostudies-literature
Project description:To identify a disease-causing paired box 6 (PAX6) gene mutation in a Chinese family affected by autosomal dominant congenital aniridia.All participants in the study, including the aniridia family and 100 unrelated senile cataract controls, received a comprehensive ophthalmic examination. Genomic DNA was extracted from their whole blood. Mutation screen in all exons and their adjacent splicing junctions of PAX6 was performed by direct sequencing of polymerase chain reaction (PCR) products. PCR products of heterozygous mutation were further cloned into T-vectors and confirmed by sequencing. Multiple alignments were performed using ClustalX to compare PAX6 protein sequences among vertebrates. MicroRNA binding sites were predicted by TargetScan.A novel heterozygous PAX6 deletion c.1251_1353del103 (p.Pro418Serfs*87) affecting exon 14 and the 3'-untranslated-region (3'-UTR) was identified in the congenital aniridia family. The mutation was exclusively observed in all affected family members but not in any unaffected family member or unrelated control. Bioinformatics analysis showed that the deletion led to remarkable changes of the PAX6 protein, including a frameshift, changes of protein sequence, and a COOH-terminal extension. Multiple alignments showed that the affected region of PAX6 shared high sequence identity (100%) among its vertebrate orthologs. The COOH-terminal extension might also affect microRNA binding sites in the 3'-UTR as predicted by TargetScan.In the current study we reported a novel PAX6 deletion resulting in an abnormal PAX6 COOH-terminal extension in the Chinese family affected by aniridia. Our findings thus add to the mutation spectrum of PAX6.
| S-EPMC3339035 | biostudies-literature
Project description:PAX6 haploinsufficiency causes aniridia, a congenital eye disorder that involves the iris, and foveal hypoplasia. Comprehensive screening of the PAX6 locus, including the non-coding regions, by next-generation sequencing revealed four deep-intronic variants with potential effects on pre-RNA splicing. Nevertheless, without a functional analysis, their pathogenicity could not be established. We aimed to decipher their impact on the canonical PAX6 splicing using in vitro minigene splicing assays and nanopore-based long-read sequencing. Two multi-exonic PAX6 constructs were generated, and minigene assays were carried out. An aberrant splicing pattern was observed for two variants in intron 6, c.357+136G>A and c.357+334G>A. In both cases, several exonization events, such as pseudoexon inclusions and partial intronic retention, were observed due to the creation or activation of new/cryptic non-canonical splicing sites, including a shared intronic donor site. In contrast, two variants identified in intron 11, c.1032+170A>T and c.1033-275A>C, seemed not to affect splicing processes. We confirmed the high complexity of alternative splicing of PAX6 exon 6, which also involves unreported cryptic intronic sites. Our study highlights the importance of integrating functional studies into diagnostic algorithms to decipher the potential implication of non-coding variants, usually classified as variants of unknown significance, thus allowing variant reclassification to achieve a conclusive genetic diagnosis.
| S-EPMC9863980 | biostudies-literature
Project description:PurposeTo reveal the underlying genetic defect in two four-generation Chinese families with aniridia and explore the pathologic mechanism.MethodsFull ophthalmic examinations were performed in two families with aniridia. The PAX6 gene was directly sequenced in patients of two families, and the detected variants were screened in unaffected family members and two hundred unrelated healthy controls. Real-time quantitative PCR was used to explore pathologic mechanisms of the two variants.ResultsAniridia, cataract, and oscillatory nystagmus were observed in patients of the two families. In addition, we observed corneal opacity and microphthalmus in family 1, and strabismus, left ectopia lentis, microphthalmus, and microcornea in family 2. Sanger sequencing detected a novel 1-bp duplication (c.50dupA) in family 1 and a novel 2-bp splice site deletion (c.765+1_765+2delGT) in family 2. Sequencing of cDNA indicated skipping of exon 9 caused by the splice site deletion, being predicted to cause a premature stop codon, as well as the duplication. The PAX6 mRNA significantly lower in patients with aniridia than in unaffected family members in both families, suggesting that the duplication and splice site deletion caused nonsense-mediated mRNA decay.ConclusionsOur study identified two novel PAX6 variants in two families with aniridia and revealed the pathogenicity of the variants; this would expand the variant spectrum of PAX6 and help us better understand the molecular basis of aniridia, thus facilitating genetic counseling.
| S-EPMC5518831 | biostudies-literature
Project description:Objective:To analyse the epidemiological trends of tuberculosis in the Siberian and Far Eastern federal districts, the areas with the highest disease burden in the Russian Federation. Methods:We applied principal coordinate analysis to study a total of 68 relevant variables on tuberculosis epidemiology, prevention and control. Data on these variables were collected over 2003-2016 in all 21 regions of the Siberian federal district and Far Eastern federal district (total population: 25.5 million) through the federal and departmental reporting system. We identified the regions with a favourable or unfavourable tuberculosis epidemiological profile and ranked them as low or high priority for specific interventions. Findings:The median number of tuberculosis notifications in the regions was 123.3 per 100?000 population (range: 54.5-265.7) in 2003, decreasing to 82.3 per 100?000 (range: 52.9-178.3) in 2016. We found large variations in the tuberculosis epidemiological profile across different regions. The principal coordinate analysis revealed that three aggregated indicators accounted for 55% of the variation. The first coordinate corresponded to tuberculosis prevalence and case notifications in the regions; the second to the severity of the disease among patients; and the third to the percentage of multidrug-resistant tuberculosis among tuberculosis patients. The regions where intervention was most urgently needed were Chukotka Autonomous Okrug, Jewish Autonomous Oblast and Tyva Republic. Conclusion:The variability in tuberculosis epidemiology across regions was likely due to differences in the quality of antituberculosis services. Precision in defining necessary interventions, as determined through the principal coordinate analysis approach, can guide focused tuberculosis control efforts.
| S-EPMC6802703 | biostudies-literature
Project description:Although HIV-1 subtype A has predominated in Russia since the end of the 20th century, other viral variants also circulate in this country. The dramatic outbreak of HIV-1 subtype G in 1988-1990 represents the origin of this variant spreading in Russia. However, full genome sequencing of the nosocomial viral variant and an analysis of the current circulating variants have not been conducted. We performed near full-length genome sequencing and phylogenetic and recombination analyses of 11 samples; the samples were determined to be subtype G based on an analysis of the pol region. Three samples were reliably obtained from patients infected during the nosocomial outbreak. The other 8 samples were obtained from patients who were diagnosed in 2010-2015. Phylogenetic analysis confirmed that a man from the Democratic Republic of the Congo was the origin of the outbreak. We also found that currently circulating viral variants that were genotyped as subtype G according to their pol region are in fact unique recombinant forms. These recombinant forms are similar to the BG-recombinants from Western Europe, particularly Spain and Portugal. The limitations of subtyping based on the pol region suggest that these viral variants are more widespread in Europe than is currently supposed.
| S-EPMC6521041 | biostudies-literature
Project description:PurposeTo explore the clinical phenotype and genetic defects of families with congenital aniridia.MethodsFour Chinese families with aniridia were enrolled in this study. The detailed ocular presentations of the patients were recorded. Whole exome sequencing (BGI MGIEasy V4 chip) was used to detect the gene mutation. Sanger sequencing was performed to validate the potential pathogenic variants, and segregation analysis was performed on all available family members.ResultsBy whole exome sequencing and Sanger sequencing, three recurrent mutations (c.112del, p.Arg38Glyfs*16; c.299G > A, p.Trp100* and c.718C > T, p.Arg240*) and one novel mutation (c.278_281del, p.Glu93Alafs*30) of PAX6 were identified. All the mutations were co-segregated with the phenotype in the families. We also observed spontaneous anterior lens capsule rupture in aniridia for the first time.ConclusionWe report spontaneous anterior lens capsule rupture as a novel phenotype of aniridia and three recurrent mutations and one novel mutation of PAX6 in families with aniridia. Our results expanded the phenotype and genotype spectra of aniridia and can help us better understand the disease.
| S-EPMC9792480 | biostudies-literature
Project description:PurposeTo identify the disease-causing gene in a four-generation Chinese family affected with autosomal dominant aniridia and cataract.MethodsAll patients underwent full ophthalmic examination. For mutation analysis, a partial coding region (exons 5-14) of paired box gene 6 (PAX6) was sequenced with DNA from the proband. Single-strand conformation polymorphism analysis for exon 5 of PAX6 was performed to demonstrate co-segregation of the PAX6 mutation with aniridia in all family members and the absence of the mutation in the normal controls.ResultsThe proband and other patients in the family were affected with aniridia accompanied with congenital cataract. A novel heterozygous PAX6 mutation in exon 5 (c.475_491del17, p.Arg38ProfsX12) was identified, which was predicted to generate a frameshift and create a premature termination codon. This mutation co-segregated with the affected individuals in the family and did not exist in unaffected family members and 100 unrelated normal controls.ConclusionsA novel deletion mutation in the PAX6 gene was identified in a Chinese family with aniridia and congenital cataract. Our study expands the mutation spectrum of PAX6.
| S-EPMC2901194 | biostudies-literature
Project description:Aniridia and congenital cataract represent rare but severe developmental ocular conditions. We examined 33 probands from France for mutations in several transcription factors associated with these phenotypes, the forkhead box E3 (FOXE3), paired box gene 6 (PAX6), paired-like homeodomain transcription factor 2 (PITX2), and paired-like homeodomain transcription factor 3 (PITX3) genes.Out of 33 probands, 27 were affected with congenital cataract while the remaining six were affected with aniridia (with or without cataract). The coding regions of FOXE3, PAX6, PITX2, and PITX3 were examined by direct DNA sequencing of gene-specific PCR products.A novel dominant mutation at the stop codon of FOXE3, c.959G>C (p.X320SerextX72), was identified in a patient with congenital cataract. Another novel FOXE3 sequence change, c.571-579dup (p.Tyr191_Pro193dup), was identified in a patient with aniridia, mild lens opacities, and some additional ocular defects; this patient was also found to carry a nonsense mutation in PAX6. PAX6 mutations were identified in two additional probands with aniridia and cataracts. None of the observed sequence alterations were found in normal controls. No mutations were identified in PITX2 or PITX3.The p.X320SerextX72 mutation is only the fourth FOXE3 allele associated with a dominant phenotype since the majority of FOXE3 mutations appear to be recessive with no phenotype observed in heterozygous carriers. The encoded protein is predicted to contain a complete normal sequence followed by seventy-two erroneous amino acids; the position and effect of this mutation are similar to two of the previously reported dominant changes, suggesting a common mechanism for dominant alleles. The p.Tyr191_Pro193dup is predicted to result in an in-frame duplication of three amino acids; however, the contribution of this mutation to the phenotype is unclear since the affected patient also carries a nonsense mutation in PAX6 which acts upstream of FOXE3 in the molecular pathway. The identified PAX6 mutations correspond to the two most commonly observed mutant alleles and demonstrate phenotypes that are consistent with the previously reported spectrum.
| S-EPMC2927439 | biostudies-literature
Project description:The aim of this study was to identify the genetic defect that is responsible for aniridia and congenital cataracts in two Tunisian families. Sequencing of the PAX6 gene in family F1 detected a novel c.265C>T transition in exon 6. In family F2, the previously described c.718C>T mutation in PAX6 was detected in the four affected members. This study adds new mutation to those previously reported in PAX6, providing further evidence for the genetic and phenotypic heterogeneity in individuals with aniridia ocular malformations.
| S-EPMC4785518 | biostudies-literature