Autosomal Dominant Aniridia Research Articles

A novel PAX6 mutation in a Chinese family with congenital aniridia

Background Aniridia is a rare congenital hereditary eye disease.Studies determined that PAX6 gene mutation is closely associated with congenital aniridia, but the mutation locus are varied. Objective This study was to identify virulence mutation locus of PAX6 gene of a Chinese family pedigree with autosomal dominant aniridia. Methods A Chinese family affected with autosomal dominant aniridia was collected and examined in Affiliated First Hospital of Zhengzhou University in August 2014.Periphery blood of 10 ml was collected from all the families and 100 unrelated health controls.The genomic DNA was extracted by standardized phenol-chloroform method, and all exons and splicing junctions of PAX6 were amplified by PCR.Real-time fluorescence quantitative PCR was performed to examine the relative expression of PAX6 mRNA in patients and normal phenotype families and health controls.This study protocol was approved by Ethic Committee of Affiliated First Hospital of Zhengzhou University and complied with Helsinki Declaration.Written informed consent was obtained from subjects or custodian before any medical examination. Results This Chinese family inclued 3 generations and 9 members, with a classic autosomal dominant inheritance mode.Five patients were found, showing the absence of iris and cataract in 3 adult patients and only absence of the iris in 2 children, and other 4 members showed the normal phenotype.A novel heterozygous PAX6 deletion mutation c. 796 del G (p.A266 fs) (GenBank ID: KP255960) in exon 10 was exclusively found in all affected individuals but not in any of the unaffected families or unrelated health controls.PAX6 mRNA level in lymphocytes was about 50% lower in aniridia patients than in unaffected family members, indicating that this mutation caused nonsense-mediated mRNA decay. Conclusions A novel deletion mutation in PAX6 gene results in an abnormal PAX6 COOH-terminal extension in the Chinese aniridia family.This finding expands the mutation spectrum of PAX6 gene. Key words: Aniridia/genetics; Chromosomes, human, pair 11/genetics; Paired box transcription factors/genetics; Base sequence; Frameshift mutation; Pedigree; Chinese/genetics

A novel PAX6 deletion in a Chinese family with congenital aniridia

Aniridia is a rare, congenital ocular disorder with the characteristics of incomplete formation of the iris caused by the mutations of the paired box gene-6 (PAX6). To investigate the clinical characterization and the underlying genetic defect in a Chinese family with autosomal dominant aniridia, we recruited the family members who underwent comprehensive ophthalmic examination. A novel heterozygous PAX6 deletion mutation c.796 del G (p.A266 fs) (GenBank ID: KP255960) in exon 10 was exclusively observed in all affected individuals but not in any of the unaffected family members or unrelated controls. The PAX6 mRNA level was about 50% lower in patients with aniridia than in unaffected family members, indicating that this mutation caused nonsense-mediated mRNA decay. In conclusion, we identified a novel deletion mutation in the PAX6 gene resulting in an abnormal PAX6 COOH-terminal extension in the Chinese family with aniridia. Our study further expands the mutation spectrum of PAX6.

A novel duplication in the PAX6 gene in a North Indian family with aniridia.

Mutations in paired box gene 6 (PAX6) are the major cause of aniridia that may be associated with several other developmental anomalies of the eye, including microcornea in rare cases. Therefore, the purpose of this study was to identify the underlying genetic cause in a two-generation North Indian family diagnosed with aniridia. All the participants enrolled in the study, including the aniridia family and 20 healthy individuals (controls), underwent a comprehensive ophthalmic examination. Mutation screening was performed for the PAX6 gene by direct sequencing of the polymerase chain reaction products. A novel PAX6 duplication in exon 5 at position c.474dupC was identified in all three affected individuals from the family but not in the unaffected family members or unrelated controls. We reported a novel duplication in the PAX6 gene capable of causing the classic aniridia phenotype. This is the first report on the duplication in a North Indian family with autosomal dominant aniridia.

Non-invasive anterior segment and posterior segment optical coherence tomography and phenotypic characterization of aniridia

Objective To determine the value of optical coherence tomography (OCT) as a diagnostic tool in the critical evaluation of phenotypic variability seen in an aniridia family with a novel PAX6 mutation. Design Genetic and observational family study. Participants Three-generation family segregating autosomal dominant aniridia. Methods Ophthalmic examination included best-corrected visual acuity, slit-lamp biomicroscopy, direct and indirect ophthalmoscopy, tonometry, and OCT. PAX6 gene mutation analysis was carried out by direct sequencing of gene-specific PCR products and protein analysis by Western blot. Results Intrafamilial variable expressivity was seen between 4 affected family members. Phenotype differences between twin children suggested that this was due to modifier gene effects rather than environment. Anterior segment OCT demonstrated a range of iridocorneal angle abnormalities and corneal thickening in only 3, but ciliary body hypoplasia in all 4 affected patients. Posterior segment OCT demonstrated dome-shaped, hypoplastic macular profiles in the 2 affected children. Novel outer retinal changes were also seen, suggestive of a phototoxic retinopathy not previously recognized in aniridia. Ocular disease segregated with a novel PAX6 Q178X nonsense mutation with Western blot analysis suggesting that this led to haploinsufficiency of PAX6 protein. Conclusions Non-contact OCT imaging allowed for a more detailed assessment of anterior and posterior segment disease in children and adults with aniridia plus nystagmus. This led to the identification of novel features and highlights a practical, non-contact strategy well suited to genotype/phenotype studies and the longitudinal management of aniridic glaucoma in children.

Screen of mutation of PAX6 in a Chinese family with autosomal dominant congenital aniridia

目的 研究PAX6基因突变是否是导致一先天性无虹膜家系致病的原因.方法 收集一先天性无虹膜家系,制备外周血基因组DNA,PCR扩增PAX6基因的外显子及其邻近的内含子,应用单链构象多态性(SSCP)法检测,如果发现变异条带,将相应的扩增产物回收并纯化后进行PAX6基因测序.测序结果与GenBank公布的PAX6基因正常序列比对,寻找有无突变.结果 本家系43名成员中有8例患病,遗传方式符合常染色体显性遗传特点,40岁以上的4例患者眼压高于35mmHg.所有患者中未发现全身并发症.在家系所有患者中均未发现异常条带.结论 PAX6基因与该先天性无虹膜家系无关.该家系的致病基因有待进一步通过全基因组扫描的方法来确定。

Autosomal Dominant Aniridia in A Nigerian Family: A Case Report.

A 54year old man brought his son to our clinic because of large eyeballs and poor vision from birth. Family history revealed that father and another child had poor vision and used to squeeze their faces especially in bright light. Examination of the boy revealed bilateral aniridia with congenital glaucoma. The father, the other child and his grand child all had bilateral aniridia with microcorneae. This is a rare case of autosomal dominant aniridia in threegenerations of a Nigerian family. Recognition of a child with aniridia should draw the attention of the ophthalmologist to the possibility of a familial disorder.Key words: Aniridia, Autosomal dominant, Alternate family members, Nigerian family.

Epidemiology of aniridia in Sweden and Norway

To investigate the epidemiology of aniridia in the populations of Sweden and Norway. A thorough search for aniridia patients has been performed in Sweden and Norway. All participants had a clinical ophthalmological examination documented through photography. Blood samples were taken for mutation analysis and pedigrees were established. A total of 181 patients with aniridia were identified in the two countries. This gives an age-specific prevalence of 1:72,000 in the entire region, 1:70,000 in Sweden and 1:76,000 in Norway. A total of 124 individuals (69%) were examined. Male/female ratio was 0.94 (Sweden 0.85 and Norway 1.2). Mean age of the examined patients was 29 years and median age 25 years. We did not find any significant age difference between the two countries. The mean visual acuity (VA) was 0.19 (Sweden 0.19 and Norway 0.18).The number of families with more than one affected member was 31 and the number of sporadic cases was 40. We have done a thorough search of the literature, but we have found no earlier studies describing aniridia in an entire country and only a few reports from larger areas. We assume that most aniridia patients have been found and the aniridia prevalence of 1:72,000 can be regarded as well supported. Further studies on other aspects of aniridia are in progress, and information from these can contribute to guidelines for the care of patients with this rare but serious disease.

Bilateral vasoproliferative retinal tumors in a patient with autosomal dominant aniridia.

To document retinal vasoproliferative tumors in a patient with aniridia. A 32-year-old woman with known autosomal dominant aniridia and lifelong visual acuity of approximately 20/80 noted further visual acuity loss. Examination revealed horizontal nystagmus and visual acuity of 20/100 in both eyes. Both eyes displayed a narrow rim of rudimentary iris with visualization of the entire lens and zonule. The cornea was clear and minimal posterior subcapsular cataract was noted. Both eyes showed diffuse retinal pigment epithelial alterations. The fovea was flat and without depression on optical coherence tomography. Inferiorly in both eyes was exudative retinal detachment from ill-defined vascular retinal tumors of approximately 15 mm diameter and 3.5 mm thickness. Both eyes were treated with plaque radiotherapy. Although aniridia typically affects the anterior segment of the eye, vision-threatening retinal detachment from vasoproliferative tumor can occur.

Aniridia associated with ptosis in three generations of the same family

Aniridia is a spectrum of abnormalities of the iris anatomy, which range from a total absence of the iris to a mild stromal hypoplasia with normal pupil. Aniridia associated with ptosis in three generations of the same family is described. The cases fit the autosomal dominant familial aniridia (AN1) type, a genetic form of congenital aniridia characterised by isolated ocular defects.

Absence of PAX6 Gene Mutations in Gillespie Syndrome (Partial Aniridia, Cerebellar Ataxia, and Mental Retardation)

The PAX6 gene is expressed at high levels in the developing eye and cerebellum and is mutated in patients with autosomal dominant aniridia. We have tested the role of PAX6 mutations in three families with Gillespie syndrome, a rare autosomal recessive condition consisting of partial aniridia, cerebellar ataxia, and mental retardation. Single-strand conformational polymorphism analysis of affected individuals revealed no alteration of PAX6 sequences. In two families, the disease trait segregates independently from chromosome 11p markers flanking PAX6. We conclude that Gillespie syndrome is genetically distinct from autosomal dominant aniridia.

Criteria to Detect Minimal Expressivity Within Families With Autosomal Dominant Aniridia

Autosomal dominant aniridia with complete penetrance without Wilms' tumor in five generations with 27 affected family members has been reassigned from chromosome 2p25 to chromosome 11p13. Clinically, aniridia was obvious in affected individuals with variable expressivity when they had rudimentary iris stumps, typical or atypical iris colobomata, or round, eccentric pupils. However, iris and retinal fluorescein angiography was required to detect abnormal vascular remodeling that resulted in incomplete iris collarettes and decreased retinal foveal avascular zones in 27 family members at risk with round, central pupils. These angiograms distinguished five affected and 22 unaffected individuals, and were the critical criteria required to detect minimal expressivity of aniridia in family members with round, central pupils.

Resolution of the two loci for autosomal dominant aniridia, AN1 and AN2, to a single locus on chromosome 11p13

Two distinct loci have been proposed for aniridia; AN1 for autosomal dominant aniridia on chromosome 2p and AN2 for the aniridia in the WAGR contiguous gene syndrome on chromosome 11p13. In this report, the kindred segregating for autosomal dominant aniridia, which suggested linkage to acid phosphatase-1 (ACP1) and led to the assignment of the AN1 locus on chromosome 2p, has been updated and expanded. Linkage analysis between the aniridia phenotype and ACP1 does not support the original linkage results, excluding linkage up to θ = 0.17 with Z = −2. Tests for linkage to other chromosome 2p markers, APOB, D2S71, D2S5, and D2S1, also excluded linkage to aniridia. Markers that have been isolated from the chromosome 11p13 region were then analyzed in this aniridia family. Two RFLPs at the D11S323 locus give significant evidence for linkage. The PvuII polymorphism detected by probe p5S1.6 detects no recombinants, with a maximum lod score of Z = 6.97 at θ = 0.00. The HaeIII polymorphism detected by the probe p5BE1.2 gives a maximum lod score of Z = 2.57 at θ = 0.00. Locus D11S325 gives a lod score of Z = 1.53 at θ = 0.00. These data suggest that a locus for aniridia (AN1) on chromosome 2p has been misassigned and that this autosomal dominant aniridia family is segregating for an aniridia mutation linked to markers in the 11p13 region.

DNA diagnosis in a family with autosomal dominant aniridia

A large family with autosomal dominant aniridia is described. One of the family members presented with reduced visual acuity, nystagmus, slightly distorted macular reflex, but normal irides and clear media. Because of the high variability in expression of aniridia, even within family, a diagnosis of aniridia could not be excluded. However linkage analysis using tightly linked chromosome 11p13 markers flanking the aniridia locus (catalase, D11S151, and D11S325) made it highly unlikely that this patient inherited the aniridia gene from his affected mother.

Autosomal dominant aniridia linked to the chromosome 11p13 markers catalase and D11S151 in a large Dutch family.

In a large pedigree with autosomal dominant aniridia, we found close linkage between the aniridia locus AN2 and the markers catalase (CAT) (zeta = 7.27 at theta = 0.00) and D11S151 (zeta = 3.86 at theta = 0.10) flanking the AN2 locus on 11p13. Positive lod scores were also obtained for the 11p13----11p14 markers D11S16 and FSHB with the linkage group CAT/AN2/D11S151. We conclude that the autosomal dominant aniridia in this family is due to a mutation at the AN2 locus on 11p13. We have excluded linkage (zeta less than -2 at theta less than 0.18) between the aniridia and the chromosome 2p25 marker D2S1 (linked to ACP1).

Autosomal Dominant Aniridia in Association With Craniopharyngioma

Aniridia or congenital absence of the iris follows an autosomal dominant inheritance pattern with a high degree of penetrance.1Most affected individuals have nystagmus, cataracts, and secondary glaucoma resulting in sharply decreased visual acuity. However, the report of an affected kindred in which 18 of 32 individuals tested had normal visual acuity suggests that there may be more than one autosomal dominant aniridia syndrome.2 About one third of cases of aniridia are thought to be the result of a new mutation, and this form of aniridia is associated with an increased incidence of Wilms' tumor and other congenital malformations.3.4The association of sporadic aniridia-Wilms' tumor and a deletion in the short arm of chromosome 11 has important implications for those interested in the genetic causes of childhood cancer5and in the two-mutation model of tumorigenesis.6In this article we report what we believe is

Variable Expressivity in Autosomal Dominant Aniridia by Clinical, Electrophysiologic, and Angiographic Criteria

Of 39 members in a family with autosomal dominant aniridia with variable expressivity, 16 members, representing 50% (15 out of 30) of those at risk, were affected. Of these, ten of 16 (63%) had visual acuity of 6/12 (20/40) or better in at least one eye, and six of 16 (37%) had visual acuity between 6/15 (20/50) and 6/60 (20/200) in at least one eye. Affected patients had nystagmus (12, 75%), cataracts (nine, 56%), strabismus (15, 94%), amblyopia (six, 37%), corneal pannus (one, 6%) glaucoma (one, 6%), macular hypoplasia (five, 31%), and optic nerve hypoplasia (one, 6%). The good visual acuity in this family indicates that absence of iris tissue is not responsible for the decreased visual acuity usually associated with aniridia. The decreased visual acuity correlates instead with a decreased macular reflex and with a decreased electroretinogram amplitude. Affected family members have abnormal persistence of vessels in the macular region angiographically, and when sufficient iris tissue is present to be studied angiographically, there are abnormal vascular loops and leakage of dye at the pupillary border.

Autosomal dominant aniridia: probable linkage to acid phosphatase-1 locus on chromosome 2.

Maximum likelihood analysis for linkage between autosomal dominant aniridia and 12 biochemical and serological markers in a single large family showed a probable linkage between autosomal dominant aniridia and the enzyme acid phosphatase-1. The presence of an autosomal dominant aniridia gene linked to acid phosphatase-1 on chromosome arm 2p and the existence of an aniridia syndrome resulting from deletion of band 13 of the short arm of chromosome 11 establishes a chromosome basis for genetic heterogeneity of aniridia phenotypes.