Aniridia 2

A number sign (#) is used with this entry because of evidence that aniridia-2 (AN2) is caused by heterozygous mutation in a PAX6 (607108) cis-regulatory element (SIMO) that resides in an intron of the adjacent ELP4 gene (606985) on chromosome 11p13. One such patient has been reported.

For a general phenotypic description and a discussion of genetic heterogeneity of aniridia, see AN1 (106210).

Clinical Features

Bhatia et al. (2013) studied a 17-year-old boy with aniridia who was diagnosed at 2 years of age with bilateral iris hypoplasia. Renal ultrasound, audiometric examination, and neurologic evaluation were normal, as were physical and psychomotor development. At 17 years of age, his bilateral aniridia was confirmed, and slit-lamp examination showed peripheral cataracts in both lenses. Funduscopic evaluation demonstrated absence of foveal depression, indicative of foveal hypoplasia, and optical coherence tomography (OCT) revealed bilateral absence of the normal depression of the optic pit. His parents were unaffected.

D'Elia et al. (2007) reported 2 Italian families segregating autosomal dominant aniridia over 3 generations. In the first family (A13), a son, father, and paternal grandfather exhibited bilateral aniridia associated with bilateral cataract and glaucoma. In the second family (A16), bilateral aniridia was present in 2 female cousins, both of their mothers and a maternal aunt, and their maternal grandmother. The grandmother also had unilateral cataract, and 1 of her daughters had bilateral cataract.

Cheng et al. (2011) examined 5 of 15 affected members from a large 5-generation Chinese family segregating autosomal dominant aniridia. In addition to aniridia, recurrent findings included optic atrophy, retinitis pigmentosa, cataract, lens subluxation, and dysplasia of the trabecular meshwork, fovea, and optic nerve. There were no apparent autistic problems or intellectual disabilities in affected individuals, and systemic evaluation excluded WAGR syndrome (194072), Axenfeld, Rieger and Peters anomalies, iridocorneal endothelial syndromes, and sclerocornea.

Cytogenetics

Fantes et al. (1995) studied 2 aniridia pedigrees in which the disease segregated with chromosomal rearrangements that involved 11p13 but did not disrupt the PAX6 gene. They isolated YAC clones that encompass the PAX6 locus and found that, in both pedigrees, the chromosomal breakpoint is at least 85 kb distal to the 3-prime end of PAX6. In addition, the open reading frame of PAX6 was apparently free of mutations. Fantes et al. (1995) proposed that the PAX6 gene on the rearranged chromosome 11 is in an inappropriate chromatin environment for normal expression, and therefore that a 'position effect' is the underlying mechanism of the anomaly in these families.

Crolla et al. (1996) described another case that suggested position effect: a sporadic aniridia patient with a translocation t(7;11). By fluorescence in situ hybridization they showed that the breakpoint in 11p13 lay between the PAX6 locus and a region approximately 100 kb distal to PAX6. No detectable deletion was found within PAX6, suggesting that the aniridia may have resulted from the distal chromatin domain containing either enhancers or regulators. Position effect variegation was reviewed by Karpen (1994).

Lauderdale et al. (2000) reported 2 submicroscopic de novo deletions of 11p13, located more than 11 kb from the 3-prime end of PAX6, that caused sporadic aniridia in unrelated patients. Clinical manifestations were indistinguishable from cases with chain-terminating mutations in the coding region. Using human-mouse retinoblastoma somatic cell hybrids, the authors showed that PAX6 is transcribed only from the normal allele but not from the deleted chromosome 11 homolog. Their findings suggested that remote 3-prime regulatory elements are required for initiation of PAX6 expression.

In 6 of 77 patients with aniridia, 2 of whom were previously studied by Crolla et al. (1997), Crolla and van Heyningen (2002) performed FISH analysis and identified deletions less than 500 kb that shared a similar proximal breakpoint within a cosmid containing the last 10 exons of PAX6 and part of the neighboring gene, ELP4. Two of the 6 patients were mosaic for the deletion.

In a 13-year-old boy with aniridia, autism, and mental retardation, Davis et al. (2008) identified a 1.3-Mb deletion approximately 35 kb distal to the last exon of PAX6; the authors noted that the deletion included the 3-prime enhancer regions characterized by Lauderdale et al. (2000) as well as 6 neighboring genes (ELP4; DPH4, 611072; DCDC1, 608062; DCDC5, 612321; MPPED2; and IMMP1L, 612323). The mutation was presumably inherited from the mother, who had aniridia as well as depression, anxiety, and social awkwardness; DNA was not available for analysis. The unaffected father did not carry the deletion.

In a large 5-generation Chinese family segregating autosomal dominant aniridia, negative for mutation in the PAX6 gene, Cheng et al. (2011) performed aCGH analysis and identified a heterozygous 556-kb deletion (chr11:31,074,403-31,640,263, NCBI36), located approximately 123 kb from the 3-prime end of PAX6, that segregated with disease in the family. The deletion encompassed 4 annotated genes, including DCDC1, DNAJC24 (611072), IMMP1L, and ELP4. Cheng et al. (2011) concluded that their findings provided further support for the existence of remote 3-prime regulatory elements downstream of the PAX6 gene.

Molecular Genetics

In a cohort of 21 Italian probands with aniridia, D'Elia et al. (2007) screened for mutations in the PAX6 gene and performed quantitative real-time PCR for deletions in the 5-prime and 3-prime regions of PAX6. In 2 unrelated patients who were negative for mutation in the PAX6 gene, they detected deletions within the ELP4 gene. In both families (A13 and A16), the deletions segregated fully with disease and were not found in 60 controls. D'Elia et al. (2007) stated that there were no significant phenotypic differences between patients with deletions 3-prime to the PAX6 gene and patients with point mutations in PAX6.

In a panel of 60 patients with aniridia without PAX6 exonic mutations or large-scale chromosomal abnormalities, Bhatia et al. (2013) screened a selection of eye-related cis-regulatory elements and identified, in a 17-year-old boy, a de novo nucleotide variant within an ultraconserved sequence, SIMO, located 150 kb downstream of PAX6 within an intron of the ELP4 gene (606985.0001).

Animal Model

Bhatia et al. (2013) generated mice and zebrafish transgenic for mutant versions of SIMO, a PAX6 cis-regulatory enhancer located within an intron of the adjacent ELP4 gene. Transgenic fish lacked signal in the lens but retained expression in other parts of the embryo. In transgenic mice, expression was lost in the lens but remained in hindbrain and diencephalon; later-stage expression in the retina was also lost.