Molecular analysis of the PAX6 gene for congenital aniridia in the Korean population: Identification of four novel mutations

Seoul St. Mary's Hospital, Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Molecular vision (Impact Factor: 1.99). 02/2012; 18(53):488-94.
Source: PubMed


To analyze the paired box gene 6 (PAX6) in Korean patients with congenital aniridia.
Genomic DNA was isolated from peripheral blood leukocytes of 22 aniridia patients in 18 unrelated families. Polymerase chain reaction was performed for all 14 exons of PAX6 followed by bidirectional sequencing.
Fourteen different kinds of mutations were detected in 16 of 18 unrelated families (mutation detection rate: 88.9%), including four novel mutations; c.658G>T (p.Glu220*), c.464delG (p.Ser155Thrfs*52), c.87_90dupTGTA (p.Glu31Cysfs*26), and c.642A>C (p.Arg214Ser), among which the former three mutations induce premature termination of PAX6 protein translation. Approximately 92.9% of identified mutations lead to the premature termination of the protein resulting from 7 nonsense mutations (50.0%), 3 splicing errors (21.4%), 2 deletions (14.3%), and 1 insertion (7.1%).
Most of the mutations identified in Korean aniridia patients lead to the premature truncation of the PAX6 protein, supporting that PAX6 protein haploinsufficiency causes the classic aniridia phenotype. We also found four novel PAX6 mutations associated with aniridia.

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Available from: Myungshin Kim, Dec 06, 2015
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    • "Due to quite the homogenous clinical symptoms and a small number of patients, we were not able to define any genotype–phenotype correlations. The findings of the current study are consistent with those of D'Elia et al. (2007), Lim et al. (2012), and Park et al. (2012), who did not find any phenotypic differences according to the identified genotype. Defining the genotype–phenotype correlation requires the analysis of a larger cohort of patients. "
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    ABSTRACT: Aniridia is a rare, bilateral, congenital ocular disorder causing incomplete formation of the iris, usually characterized by iris aplasia/hypoplasia. It can also appear with other ocular anomalies, such as cataracts, glaucoma, corneal pannus, optic nerve hypoplasia, macular hypoplasia, or ectopia lentis. In the majority of cases, it is caused by mutation in the PAX6 gene, but it can also be caused by microdeletions that involve the 11p13 region. Twelve unrelated patients of Polish origin with a clinical diagnosis of aniridia were screened for the presence of microdeletions in the 11p13 region by means of multiplex ligation probe amplification (MLPA). Additionally, the coding regions of the PAX6 gene were sequenced in all probands. MLPA examination revealed different size deletions of the 11p13 region in five patients. In three cases, deletions encompassed the entire PAX6 gene and a few adjacent genes. In one case, a fragment of the PAX6 gene was deleted only. In the final case, the deletion did not include any PAX6 sequence. Our molecular findings provide further evidence of the existence of the distant 3' regulatory elements in the downstream region of the PAX6 gene, which is known from other studies to influence the level of protein expression. Sequence analysis of the PAX6 gene revealed the three different point mutations in the remaining four patients with aniridia. All the detected mutations were reported earlier. Based on accomplished results, the great diversity of the molecular basis of aniridia was found. It varies from point mutations to different size deletions in the 11p13 region which encompass partly or completely the PAX6 gene or cause a position effect.
    Preview · Article · Jun 2013 · Journal of applied genetics
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    ABSTRACT: 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. 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. 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. 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.
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    ABSTRACT: To report 3 cases with unusual ophthalmic phenotypes of congenital aniridia. Interventional case series. A 10-day-old infant with cloudy and large cornea in both eyes, 1 month-old male with bilateral corneal opacity, and 27-year-old male with low vision. Complete ophthalmic examination and genetic evaluation. Case 1 was a neonate with concurrent presentation of congenital aniridia and glaucoma. Case 2 was diagnosed as congenital aniridia combined with Peters anomaly in both eyes. Case 3 had 2 unusual features of aniridia, which were asymmetric iris involvement and absence of limbal deficiency. It is important to perform thorough ophthalmologic evaluations in patients with congenital aniridia because of the possibilities of coexistence of other ocular abnormalities.
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