A recurrent PAX6 mutation is associated with aniridia and congenital progressive cataract in a Chinese family

Abstract

Purpose: Aniridia is phenotyically and genetically heterogeneous. This study is to summarize the phenotypes and identify the genetic defect responsible for aniridia and congenital progressive cataract in a three generation Chinese family.

Methods: A detailed family history and clinical data from patients were collected by ophthalmologic examination, including visual acuity, slit-lamp examination, tonometer, keratometry, corneal topography, optical coherence tomography, and ultrasonic A/B scan. All exons and flanking intronic sequences of the paired box 6 (PAX6) gene were amplified by polymerase chain reaction (PCR) and screened for mutation by direct DNA sequencing. Structure and function of the mutant PAX6 were analyzed by bioinformatics analysis.

Results: All the six patients shared common manifestations of complete aniridia, congenital cataract and thickened cornea, and broad phenotypic variability was observed in nystagmus, ptosis, strabismus, glaucoma, corneal pannus, corneal curvature, corneal vascularization, cataract subtype, ectopia lentis, axial length, and optic disc anomalies. Sequencing of the candidate gene detected a heterozygous c.307C>T transition in the coding region of PAX6, resulting in the substitution of a highly conserved arginine codon for a termination codon (p.R103X). The p.P103X mutation co-segregated with the affected individuals in the family. The change was supposed to cause structural and functional changes based on computational analysis.

Conclusions: We identified a recurrent PAX6 c.307C>T mutation in an aniridia and congenital progressive cataract family, and summarized the variable phenotypes among the patients, which expanded the phenotypic spectrum of aniridia in a different ethnic background.

Figure 1

Pedigree of the aniridia and congenital progressive cataract. It is inherited as an autosomal dominant trait. The proband is marked with an arrow. Squares and circles indicate males and females respectively. Black and white symbols represent affected and unaffected individuals, respectively.

Figure 2

Slip lamp photographs of all the affected individuals. All the affected patients are had complete aniridia. The phenotypes are described and summarized in Table 2.

Figure 3

Sequencing results of the PAX6 gene. A: The sequence of an affected member (individual II:4) is shown. B: The sequence of an unaffected member (II:3) is shown. A heterozygous mutation (c.307C>T) is detected in the exon 6 of PAX6.

Figure 4

Multiple-sequence alignment in PAX6 from 8 different species. It demonstrates that R103 is highly conserved (highlighted in red).

Figure 5

Stuctural modeling of the PAX6 paired domain. Cylinders and arrows represent α helices and β strands, respectively. The orange double helix in the center denotes DNA. The red segment represents the mutation point (R103). The structural model by PyMOL analysis shows the relationship between PAX6 paired domain and DNA.