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The Ocular Surface Jan 2020To investigate corneal phenotype in aniridia-associated keratopathy (AAK) including its earliest manifestations, in relation to PAX6 mutational status.
PURPOSE
To investigate corneal phenotype in aniridia-associated keratopathy (AAK) including its earliest manifestations, in relation to PAX6 mutational status.
METHODS
46 subjects (92 eyes) with congenital aniridia from a German registry were examined using slit lamp biomicroscopy, anterior segment optical coherence tomography, contact esthesiometry and in vivo confocal microscopy. Cytogenetic analysis was conducted by Sanger sequencing of PAX6 exons and/or MLPA analysis. Measured parameters included AAK grade, distance-corrected visual acuity (DCVA), central corneal thickness (CCT), corneal sensitivity, subbasal nerve density, mature dendritic cell (DC) density and corneal epithelial phenotype.
RESULTS
46 subjects (age range: 1-64 years) were examined, including 23 (50%) children under the age of 18. Five subjects (11.1%) with absent PAX6 coding mutation (non-PAX6 cases) had mild AAK (Grade 0-1) into the fourth decade of life and maintained corneal epithelial phenotype, greater subbasal nerve density (16.8 mm/mm vs. 3.58 mm/mm, P = 0.01) and better corneal sensitivity (41 ± 11 mm vs. 28 ± 12 mm, P = 0.03) relative to those with PAX6 coding mutations. In five subjects, corneal endothelial cell density ranged from 3245 to 4399 cells/mm. Independent of mutational status, an increased CCT, over tenfold increased mature DC density and reduced corneal sensitivity characterized all subjects.
CONCLUSIONS
PAX6 coding mutations influence AAK phenotype and progression from the earliest stages of life. A minimal keratopathy present in 100% of congenital aniridia cases is independent of the specific mutation and consists of increased corneal thickness, reduced touch sensitivity, and increased ocular surface immune activity.
Topics: Adolescent; Adult; Aniridia; Child; Child, Preschool; Cornea; Corneal Diseases; Humans; Infant; Middle Aged; Mutation; PAX6 Transcription Factor; Phenotype; Young Adult
PubMed: 31734509
DOI: 10.1016/j.jtos.2019.11.002 -
Molecular Vision 2020Aniridia is a rare congenital panocular disease caused by mutations in . The purposes of this study were to clarify the mutation features of in a cohort of Chinese...
PURPOSE
Aniridia is a rare congenital panocular disease caused by mutations in . The purposes of this study were to clarify the mutation features of in a cohort of Chinese patients with aniridia and to describe their clinical characteristics.
METHODS
We recruited 95 patients from 65 unrelated families clinically diagnosed with aniridia. All patients underwent ophthalmic examinations. Sanger sequencing and multiplex ligation probe amplification of were performed to detect intragenic variants and copy number variations (CNVs).
RESULTS
We identified 58 disease-causing mutations in in 63 families; the detection rate was 96.9%. The 58 mutations included frameshift indels (27.6%), splice site changes (25.9%), nonsense mutations (20.7%), CNVs (19.0%), missense mutations (3.4%), run-on mutations (1.7%), and a synonymous mutation (1.7%). Clinical examinations revealed that 71 patients had complete or almost complete iris loss, 16 patients showed partial iris loss, and six patients had a full iris but with an abnormal structure.
CONCLUSIONS
The results confirmed that mutations in are the predominant cause of aniridia, and the majority are loss-of-function mutations that usually result in classical aniridia. In contrast, missense mutations, run-on mutations, and small numbers of splicing mutations mostly lead to atypical aniridia and an intrafamilial phenotypic variability of iris hypoplasia.
Topics: Adolescent; Adult; Aged; Aniridia; Asian People; Cell Line; Child; Child, Preschool; Codon, Nonsense; Cohort Studies; DNA Copy Number Variations; Female; Frameshift Mutation; Genetic Association Studies; Humans; INDEL Mutation; Infant; Iris; Male; Middle Aged; Mutation, Missense; PAX6 Transcription Factor; RNA Splicing; Sequence Analysis, DNA; Silent Mutation
PubMed: 32214788
DOI: No ID Found -
Molecular Vision 2015Aniridia is a rare panocular disorder characterized by iris hypoplasia and other associated eye anomalies. Heterozygous null mutations in paired box gene 6 (PAX6) are...
PURPOSE
Aniridia is a rare panocular disorder characterized by iris hypoplasia and other associated eye anomalies. Heterozygous null mutations in paired box gene 6 (PAX6) are the major cause of the classic aniridia phenotype. This study aims to detect the mutational spectrum of PAX6 and associated phenotypes in southern Indian patients with sporadic and familial aniridia.
METHODS
Genomic DNA was isolated from peripheral blood from all participants. The coding regions and flanking intronic sequences of PAX6 were screened with Sanger sequencing in 30 probands with aniridia. The identified variations were further evaluated in available family members and 150 healthy controls. The pathogenic potential of the mutations were assessed using bioinformatics tools.
RESULTS
Thirteen different mutations were detected in eight sporadic and five familial cases. Eleven novel mutations, including five insertions (c.7_10dupAACA, c.567dupC, c.704dupC, c.868dupA and c.753_754insTA), two deletions (c.242delC and c.249delT), and four splicing variants (c.10+1G>A, c.141G>A, c.141+4A>G and c.764A>G) were identified in this study. Clinical findings of the patients revealed phenotypic heterogeneity with the same or different mutations.
CONCLUSIONS
This study reported 11 novel mutations and thus expanded the spectrum of PAX6 mutations. Interestingly, all mutations reported in this study were truncations, which confirms the hypothesis that haploinsufficiency of PAX6 causes the aniridia phenotype. Our observations revealed inter- and intrafamilial phenotypic variability with PAX6 mutations. The common ocular findings associated with PAX6 mutations were iris hypoplasia, nystagmus, and foveal hypoplasia reported in almost all cases, with cataract, glaucoma, and keratopathy reported in approximately 50% of the patients.
Topics: Adolescent; Adult; Aged; Amino Acid Sequence; Aniridia; Base Sequence; Case-Control Studies; Cataract; Child; Child, Preschool; DNA Mutational Analysis; Eye Diseases, Hereditary; Eye Proteins; Female; Fovea Centralis; Genetic Association Studies; Genetic Heterogeneity; Glaucoma; Haploinsufficiency; Homeodomain Proteins; Humans; India; Infant; Introns; Iris; Male; Middle Aged; Molecular Sequence Data; Mutation; Nystagmus, Congenital; Nystagmus, Pathologic; Open Reading Frames; PAX6 Transcription Factor; Paired Box Transcription Factors; Repressor Proteins; Retinal Diseases
PubMed: 25678763
DOI: No ID Found -
Health Psychology and Behavioral... 2023Congenital aniridia is a rare genetic disorder of the eye characterized by visual impairment and progressive vision loss. While prior research has focused on ocular...
BACKGROUND
Congenital aniridia is a rare genetic disorder of the eye characterized by visual impairment and progressive vision loss. While prior research has focused on ocular manifestations in individuals with aniridia, there is a dearth of research on impacts on cognition and mental health. The aims of this study were to describe subjective symptoms of everyday executive functioning, fatigue and sleepiness in adults with aniridia and to compare self-reported health status with that of a normative reference group.
METHODS
Twenty-nine adults (aged 18-79 years) with congenital aniridia were included in this online survey, of whom 52% were females. Participants completed self-report measures of executive functioning (The Behavior Rating Inventory of Executive Function-Adult Version), sleepiness, fatigue, and health status (EQ-5D-5L).
RESULTS
Participants reported relatively few problems in everyday executive functioning, with only 14% experiencing impaired executive functioning. Scores on the five EQ-5D-5L domains (mobility, self-care, usual activities, pain, and anxiety/depression) did not differ from those of the normative reference group. The frequencies of excessive daytime sleepiness and severe fatigue were 17% and 38%, respectively. Ocular pain was experienced by 62% of participants.
CONCLUSIONS
The findings show that cognitive problems are related to and reflect self-reported health status and extent of fatigue. Moreover, those who suffered from ocular pain reported more difficulties with executive functioning, sleepiness and fatigue. These findings are important for understanding this disorder and supporting patients.
PubMed: 37811316
DOI: 10.1080/21642850.2023.2263534 -
Folia Biologica 2020The aim of this study was to report PAX6 disease-causing variants in six Czech families, to describe the associated phenotypes, and to perform functional assessment of...
The aim of this study was to report PAX6 disease-causing variants in six Czech families, to describe the associated phenotypes, and to perform functional assessment of the splice site variants. Detailed ophthalmic examination was performed. The PAX6 coding region was directly sequenced in three probands. Two probands were analysed by exome sequencing and one by genome sequencing. The effect of two variants on pre-mRNA splicing was evaluated using an exon trapping assay. Six different heterozygous PAX6 variants were identified, with c.111_120del and c.1183+1G˃T being novel. Both c.1183+1G˃T and c.1032+1G>A were proved to cause aberrant splicing with exon skipping and subsequent frameshift. The phenotypic features were variable between and within families. One individual, aged 31 years, presented with mild unilateral ptosis accompanied by aniridia in the right eye, partial aniridia in the left eye, and bilateral congenital cataracts, without marked foveal hypoplasia. Bilateral microcornea, partial aniridia, congenital cataracts, and a large posterior segment coloboma were found in another proband, aged 32 years. One child, aged 8 years, had bilateral high myopia, optic nerve colobomas, anterior polar cataracts, but no iris defects. Another individual, aged 46 years, had bilateral congenital ptosis, iris hypoplasia, keratopathy with marked fibrovascular pannus, anterior polar cataract, and foveal hypoplasia combined with impaired glucose tolerance. However, his daughter, aged 11 years, showed classical features of aniridia. Our study extends the genetic spectrum of PAX6 disease-causing variants and confirms that the associated phenotypic features may be very broad and different to the 'classical' aniridia.
Topics: Adult; Aniridia; Child; Czech Republic; Eye Proteins; Female; Humans; Male; Middle Aged; Mutation; PAX6 Transcription Factor; Pedigree; Phenotype; RNA Splicing
PubMed: 33745259
DOI: No ID Found -
Molecular Vision 2011To identify mutations in the paired box 6 (PAX6) gene of 33 probands with aniridia and to reveal the mutational spectrum in the Chinese population.
PURPOSE
To identify mutations in the paired box 6 (PAX6) gene of 33 probands with aniridia and to reveal the mutational spectrum in the Chinese population.
METHODS
Unrelated probands with aniridia from 27 newly selected families and six previously analyzed families participated in this study. The coding regions of PAX6 in the 27 new families were analyzed using cycle sequencing. Families that lacked detectable variations based on sequencing (14 new and six previously analyzed) were further analyzed using multiplex ligation-dependent probe amplification (MLPA).
RESULTS
Fifteen mutations were identified in 16 of the 33 families: c.[65_94del30; 99_105dup7], c.101_102insA, c.177delG, c.238_239insGCGA, c.1033-42_1033-26del17insG, c.1A>G, c.120C>A, c.718C>T, c.949C>T, c.1062C>A, c.1183G>A, c.1268A>T, and three gross deletions involving exons 1-14, exons 8-14, and exons 9-14. The first five mutations were novel and the c.1268A>T mutation was present in two families. Phenotypic variations were observed between families and between different affected patients within the families.
CONCLUSIONS
The PAX6 mutation spectrum in Chinese aniridia patients is comparable to that reported in other ethnic groups. Further studies of the 17 families with no detected mutations may provide additional information to improve the understanding of the molecular genetics of aniridia.
Topics: Adolescent; Alleles; Aniridia; Asian People; Base Sequence; Child; Child, Preschool; DNA Mutational Analysis; Exons; Eye Proteins; Female; Gene Frequency; Genetic Heterogeneity; Genetic Testing; Haplotypes; Homeodomain Proteins; Humans; Male; Molecular Sequence Data; Multiplex Polymerase Chain Reaction; Mutation; PAX6 Transcription Factor; Paired Box Transcription Factors; Pedigree; Phenotype; Repressor Proteins; Sequence Deletion; Young Adult
PubMed: 21850189
DOI: No ID Found -
Ophthalmology. Retina Jun 2019Investigate in vivo cone photoreceptor structure in familial aniridia caused by deletion in the PAX6 gene to elucidate the complexity of between-individual variation in...
PURPOSE
Investigate 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.
DESIGN
Descriptive case-control study.
PARTICIPANTS
Eight 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).
METHODS
DNA 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 MEASURES
Within-family variability in macular retinal layer thicknesses, cone photoreceptor density, and mosaic regularity in aniridia compared with normal control participants.
RESULTS
DNA 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/mm 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.
CONCLUSIONS
The 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.
Topics: Adolescent; Adult; Aged; Aniridia; Case-Control Studies; Cell Count; DNA; DNA Mutational Analysis; Female; Gene Deletion; Genotype; Humans; Male; Middle Aged; Ophthalmoscopy; PAX6 Transcription Factor; Phenotype; Retinal Cone Photoreceptor Cells; Tomography, Optical Coherence; Visual Acuity; Young Adult
PubMed: 31174676
DOI: 10.1016/j.oret.2019.01.020 -
Journal of Medical Genetics Jul 1988High resolution prometaphase chromosome banding has allowed the detection of discrete chromosome aberrations which escaped earlier metaphase examinations. Consistent... (Review)
Review
High resolution prometaphase chromosome banding has allowed the detection of discrete chromosome aberrations which escaped earlier metaphase examinations. Consistent tiny deletions have been detected in some well established malformation syndromes: an interstitial deletion in 15q11/12 in the majority of patients with the Prader-Willi syndrome and in a minority of patients with the Angelman (happy puppet) syndrome; a terminal deletion of 17p13.3 in most patients examined with the Miller-Dieker syndrome; an interstitial deletion of 8q23.3/24.1 in a large majority of patients with the Giedion-Langer syndrome; an interstitial deletion of 11p13 in virtually all patients with the WAGR (Wilms' tumour-aniridia-gonadoblastoma-retardation) syndrome; and an interstitial deletion in 22q11 in about one third of patients with the DiGeorge sequence. In addition, a combination of chromosome prometaphase banding and DNA marker studies has allowed the localisation of the genes for retinoblastoma and for Wilms' tumour and the clarification of both the autosomal recessive nature of the mutation and the possible somatic mutations by which the normal allele can be lost in retina and kidney cells. After a number of X linked genes had been mapped, discrete deletions in the X chromosome were detected by prometaphase banding with specific attention paid to the sites of the gene(s) in males who had from one to up to four different X linked disorders plus mental retardation. Furthermore, the detection of balanced translocations in probands with disorders caused by autosomal dominant or X linked genes has allowed a better insight into the localisation of these genes. In some females with X linked disorders, balanced X; autosomal translocations have allowed the localisation of X linked genes at the breakpoint on the X chromosome. Balanced autosome; autosome translocations segregating with autosomal dominant conditions have provided some clues to the gene location of these conditions. In two conditions, Greig cephalopolysyndactyly and dominant aniridia, two translocation families with one common breakpoint have allowed quite a confident location of the genes at the common breakpoint at 7p13 and 11p13, respectively.
Topics: Chromosome Aberrations; Chromosome Banding; Chromosome Deletion; Chromosome Disorders; Chromosome Mapping; Genetic Markers; Humans; Karyotyping; Sex Chromosome Aberrations; Syndrome; Translocation, Genetic
PubMed: 3050093
DOI: 10.1136/jmg.25.7.454 -
JCI Insight Jul 2021Aniridia is most commonly caused by haploinsufficiency of the PAX6 gene, characterized by variable iris and foveal hypoplasia, nystagmus, cataracts, glaucoma, and... (Observational Study)
Observational Study
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.
Topics: Adolescent; Adult; Aniridia; Cataract; Child; DNA Mutational Analysis; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Fovea Centralis; Genetic Association Studies; Glaucoma; Haploinsufficiency; Heterozygote; Humans; Longitudinal Studies; Male; Middle Aged; Nystagmus, Congenital; PAX6 Transcription Factor; Pedigree; Young Adult
PubMed: 34101622
DOI: 10.1172/jci.insight.148406 -
Comparison between Cultivated Oral Mucosa and Ocular Surface Epithelia for COMET Patients Follow-Up.International Journal of Molecular... Jul 2023Total bilateral Limbal Stem Cell Deficiency is a pathologic condition of the ocular surface due to the loss of corneal stem cells. Cultivated oral mucosa epithelial...
Total bilateral Limbal Stem Cell Deficiency is a pathologic condition of the ocular surface due to the loss of corneal stem cells. Cultivated oral mucosa epithelial transplantation (COMET) is the only autologous successful treatment for this pathology in clinical application, although abnormal peripheric corneal vascularization often occurs. Properly characterizing the regenerated ocular surface is needed for a reliable follow-up. So far, the univocal identification of transplanted oral mucosa has been challenging. Previously proposed markers were shown to be co-expressed by different ocular surface epithelia in a homeostatic or perturbated environment. In this study, we compared the transcriptome profile of human oral mucosa, limbal and conjunctival cultured holoclones, identifying Paired Like Homeodomain 2 () as a new marker that univocally distinguishes the transplanted oral tissue from the other epithelia. We validated PITX2 at RNA and protein levels to investigate 10-year follow-up corneal samples derived from a COMET-treated aniridic patient. Moreover, we found novel angiogenesis-related factors that were differentially expressed in the three epithelia and instrumental in explaining the neovascularization in COMET-treated patients. These results will support the follow-up analysis of patients transplanted with oral mucosa and provide new tools to understand the regeneration mechanism of transplanted corneas.
Topics: Humans; Mouth Mucosa; Follow-Up Studies; Epithelial Cells; Cells, Cultured; Epithelium; Stem Cell Transplantation; Transplantation, Autologous
PubMed: 37511281
DOI: 10.3390/ijms241411522