Similar Datasets
Project description:Purpose: To evaluate conjunctival cell microRNA and mRNA expression in relation to observed phenotype and genotype of aniridia-associated keratopathy (AAK) in a cohort of subjects with congenital aniridia. Methods: Using impression cytology, bulbar conjunctival cells were sampled from 20 subjects with congenital aniridia and 20 age and sex-matched healthy control subjects. RNA was extracted and microRNA and mRNA analysis was performed using microarrays. Results were related to the presence and severity of AAK determined by a standardized clinical grading scale and to the genotype (PAX6 mutation?) determined by clinical genetics. Results: Of the 2549 microRNAs analyzed, 21 were differentially expressed relative to controls. Among these miR-204-5p, an inhibitor of corneal neovascularization, was downregulated 26.8-fold, while miR-5787 and miR-224-5p were upregulated 2.8 and 2.4-fold relative to controls, respectively. At the mRNA level, 539 transcripts were differentially expressed, among these FOSB and FOS were upregulated 17.5 and 9.7-fold respectively, and JUN by 2.9-fold, all components of the AP-1 transcription factor complex. Pathway analysis revealed dysregulation of several enriched pathways including PI3K-Akt, MAPK, and Ras signaling pathways in aniridia. For several microRNAs and transcripts, expression levels aligned with AAK severity, while in very mild cases with missense or non-PAX6 coding mutations, gene expression was only minimally altered. Conclusion: In aniridia, specific factors and pathways are strongly dysregulated in conjunctival cells, suggesting that the conjunctiva in aniridia is abnormally maintained in a pro-angiogenic and proliferative state, promoting the aggressivity of AAK in a mutation-dependent manner. Transcriptional profiling of conjunctival cells at the microRNA and mRNA levels presents a powerful, minimally-invasive means to assess the regulation of cell dysfunction at the ocular surface.
2020-06-05 | GSE137995 | GEO
Project description:Purpose: To evaluate conjunctival cell microRNA and mRNA expression in relation to observed phenotype and genotype of aniridia-associated keratopathy (AAK) in a cohort of subjects with congenital aniridia. Methods: Using impression cytology, bulbar conjunctival cells were sampled from 20 subjects with congenital aniridia and 20 age and sex-matched healthy control subjects. RNA was extracted and microRNA and mRNA analysis was performed using microarrays. Results were related to the presence and severity of AAK determined by a standardized clinical grading scale and to the genotype (PAX6 mutation?) determined by clinical genetics. Results: Of the 2549 microRNAs analyzed, 21 were differentially expressed relative to controls. Among these miR-204-5p, an inhibitor of corneal neovascularization, was downregulated 26.8-fold, while miR-5787 and miR-224-5p were upregulated 2.8 and 2.4-fold relative to controls, respectively. At the mRNA level, 539 transcripts were differentially expressed, among these FOSB and FOS were upregulated 17.5 and 9.7-fold respectively, and JUN by 2.9-fold, all components of the AP-1 transcription factor complex. Pathway analysis revealed dysregulation of several enriched pathways including PI3K-Akt, MAPK, and Ras signaling pathways in aniridia. For several microRNAs and transcripts, expression levels aligned with AAK severity, while in very mild cases with missense or non-PAX6 coding mutations, gene expression was only minimally altered. Conclusion: In aniridia, specific factors and pathways are strongly dysregulated in conjunctival cells, suggesting that the conjunctiva in aniridia is abnormally maintained in a pro-angiogenic and proliferative state, promoting the aggressivity of AAK in a mutation-dependent manner. Transcriptional profiling of conjunctival cells at the microRNA and mRNA levels presents a powerful, minimally-invasive means to assess the regulation of cell dysfunction at the ocular surface.
2020-06-05 | GSE137996 | GEO
Project description:Conjunctival mRNA and miRNA expression profiles in congenital aniridia are genotype and phenotype dependent
| PRJNA574121 | ENA
Project description:Conjunctival mRNA and miRNA expression profiles in congenital aniridia are genotype and phenotype dependent (AKK miRNA)
| PRJNA574124 | ENA
Project description:Conjunctival mRNA and miRNA expression profiles in congenital aniridia are genotype and phenotype dependent (AKK mRNA)
| PRJNA574127 | ENA
Project description:The objective of this study was to investigate the genotype-phenotype correlation of the PAX6 gene in aniridia. We clinically examined 5 families and 16 sporadic patients with aniridia. We performed chromosomal analysis and PCR analysis of the PAX6 gene using patient genomic DNA. Chromosomal analysis demonstrated deletions at 11p13 in one allele in four sporadic patients. Seven nonsense mutations, two frameshifts (two insertions), four splice junction errors and two missense mutations were found, and all were heterozygous. The iris phenotype ranged from total to normal in each patient, and the characteristic phenotypes, including cataract, glaucoma or optic nerve hypoplasia, varied widely even among members of the same family. Foveal hypoplasia was detected in all patients except for one. No obvious genotype-phenotype correlation was identified; however, the aniridia phenotype between the two eyes in each patient was quite similar in all patients. Because PAX6 regulates numerous downstream genes and its expression is regulated by several factors during eye development, the aniridia phenotype may be complex even in family members. However, because PAX6 regulation, resulting from both paternal and maternal alleles associated with PAX6, is considered to be roughly similar in both eyes of each patient, the aniridia phenotype may be similar in both eyes of each patient.
| S-EPMC4760117 | biostudies-literature
Project description:PurposeInvestigate in vivo cone photoreceptor structure in familial aniridia caused by deletion in the PAX6 gene to elucidate the complexity of between-individual variation in retinal phenotype.DesignDescriptive case-control study.ParticipantsEight persons with congenital aniridia (40-66 yrs) from 1 family and 33 normal control participants (14-69 yrs), including 7 unaffected family members (14-53 yrs).MethodsDNA was isolated from saliva samples and used in polymerase chain reaction analysis to amplify and sequence exons and intron or exon junctions of the PAX6 gene. High-resolution retinal images were acquired with OCT and adaptive optics scanning light ophthalmoscopy. Cone density (CD; in cones per square millimeter) and mosaic regularity were estimated along nasal-temporal meridians within the central 0° to 5° eccentricity. Horizontal spectral-domain OCT line scans were segmented to analyze the severity of foveal hypoplasia (FH) and to measure retinal layer thicknesses.Main outcomes and measuresWithin-family variability in macular retinal layer thicknesses, cone photoreceptor density, and mosaic regularity in aniridia compared with normal control participants.ResultsDNA sequencing revealed a known PAX6 mutation (IV2-2delA). Those with aniridia showed variable iris phenotype ranging from almost normal appearance to no iris. Four participants with aniridia demonstrated FH grade 2, 2 demonstrated grade 3 FH, and 1 demonstrated grade 4 FH. Visual acuity ranged from 0.20 to 0.86 logarithm of the minimum angle of resolution. Adaptive optics scanning light ophthalmoscopy images were acquired from 5 family members with aniridia. Foveal CD varied between 19 899 and 55 128 cones/mm2 with overlap between the foveal hypoplasia grades. Cone density was 3 standard deviations (SDs) or more less than the normal mean within 0.5°, 2 SDs less than the normal mean at 0.5° to 4°, and more than 1 SD less than the normal mean at 5° retinal eccentricity.ConclusionsThe results showed considerable variability in foveal development within a family carrying the same PAX6 mutation. This, together with the structural and functional variability within each grade of foveal hypoplasia, underlines the importance of advancing knowledge about retinal cellular phenotype in aniridia.
| S-EPMC6557282 | biostudies-literature
Project description:Aniridia is most commonly caused by haploinsufficiency of the PAX6 gene, characterized by variable iris and foveal hypoplasia, nystagmus, cataracts, glaucoma, and aniridia-related keratopathy (ARK). Genotype-phenotype correlations have previously been described; however, detailed longitudinal studies of aniridia are less commonly reported. We identified 86 patients from 62 unrelated families with molecularly confirmed heterozygous PAX6 variants from a UK-based single-center ocular genetics service. They were categorized into mutation groups, and a retrospective review of clinical characteristics (ocular and systemic) from baseline to most recent was recorded. One hundred and seventy-two eyes were evaluated, with a mean follow-up period of 16.3 ± 12.7 years. Nystagmus was recorded in 87.2% of the eyes, and foveal hypoplasia was found in 75%. Cataracts were diagnosed in 70.3%, glaucoma in 20.6%, and ARK in 68.6% of eyes. Prevalence, age of diagnosis and surgical intervention, and need for surgical intervention varied among mutation groups. Overall, the missense mutation subgroup had the mildest phenotype, and surgically naive eyes maintained better visual acuity. Systemic evaluation identified type 2 diabetes in 12.8% of the study group, which is twice the UK prevalence. This is the largest longitudinal study of aniridia in the UK, and as such, it can provide insights into prognostic indicators for patients and guiding clinical management of both ocular and systemic features.
| S-EPMC8410060 | biostudies-literature
Project description:Generalised lipodystrophy of the Berardinelli-Seip type (BSCL) is a rare autosomal recessive human disorder with severe adverse metabolic consequences. A gene on chromosome 9 (BSCL1) has recently been identified, predominantly in African-American families. More recently, mutations in a previously undescribed gene of unknown function (BSCL2) on chromosome 11, termed seipin, have been found to be responsible for this disorder in a number of European and Middle Eastern families. We have studied the genotype/phenotype relationships in 70 affected subjects from 44 apparently unrelated pedigrees of diverse ethnic origin. In all subjects, hepatic dysfunction, hyperlipidaemia, diabetes mellitus, and hypertrophic cardiomyopathy were significant contributors to morbidity with no clear differences in their prevalence between subjects with BSCL1 or BSCL2 and those with evidence against cosegregation with either chromosome 9 or 11 (designated BSCLX). BSCL2 appears to be a more severe disorder than BSCL1 with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. Notably, subjects with BSCL2 had a significantly higher prevalence of intellectual impairment than those with BSCL1 or BSCLX (p<0.0001, OR 17.0, CI 3.6 to 79.0). The higher prevalence of intellectual impairment and the increased risk of premature death in BSCL2 compared to BSCL1 emphasise the importance of molecular diagnosis of this syndrome and have clear implications for genetic counselling.
| S-EPMC1734991 | biostudies-other
Project description:PurposeTo describe the clinical and genetic findings in two Chinese families with aniridia and other ocular abnormalities.MethodsTwo unrelated families were examined clinically. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Mutation screening of all exons of the PAX6 (paired box gene 6) gene was performed by direct sequencing of PCR-amplified DNA fragments. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect large deletions. Linkage analysis was used to validate the large deletions revealed by MLPA in all available family members.ResultsClinical examination and pedigree analysis revealed one four-generation family (85) and one three- generation family (86) with total aniridia, congenital cataracts, foveal hypoplasia, and glaucoma. No mutation in PAX6 was identified after PCR-sequencing. Through MLPA analysis, a large deletion including the whole PAX6 gene, DKFZp686k1684 (hypothetical LOC440034), and the RCN1 (reticulocalbin 1) gene was detected in family 85; a 3' deletion to the PAX6 gene including the ELP4 (elongator complex protein 4) and the DCDC1 (doublecortin domain containing 1) gene was identified in family 86.The two large deletions were confirmed with linkage analysis and the "loss of heterozygous" in the different PAX6 regions were co-segregated with the phenotype of the two families, respectively.ConclusionsPatients with the PAX6 contiguous gene deletion, including the RCN1 gene, presented more severe vision impairments than those carrying the PAX6 3' deletion. Large deletions may account for several Chinese families and sporadic cases with aniridia and screening for these kinds of alterations should be included in aniridia patients' analyses.
| S-EPMC3044699 | biostudies-literature