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Other entities represented in this entry:
SNOMEDCT: 253231007; ORPHA: 250923; DO: 0070532;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p13 | Cataract with late-onset corneal dystrophy | 106210 | Autosomal dominant | 3 | PAX6 | 607108 |
| 11p13 | Aniridia | 106210 | Autosomal dominant | 3 | PAX6 | 607108 |
A number sign (#) is used with this entry because of evidence that aniridia-1 (AN1) is caused by heterozygous mutation in the PAX6 gene (607108) on chromosome 11p13.
Although called aniridia, this disorder is a panocular one taking its name from the noticeable iris hypoplasia seen in most cases. This feature can range from a readily visible, almost complete absence of the iris, through enlargement and irregularity of the pupil mimicking a coloboma, to small slit-like defects in the anterior layer seen only on transillumination with a slit-lamp. The effect on vision is similarly variable (summary by Jordan et al., 1992).
Genetic Heterogeneity of Aniridia
There is also evidence that aniridia-2 (AN2) is caused by mutation in a PAX6 cis-regulatory element (SIMO) that resides in an intron of the adjacent ELP4 gene (606985), and that aniridia-3 (AN3) is caused by mutation in the TRIM44 gene (612298) on chromosome 11p13.
See also Gillespie syndrome (206700), in which aniridia is associated with cerebellar ataxia and mental retardation.
Shaw et al. (1960) ascertained 176 cases of aniridia in the lower Michigan peninsula. Forty isolated cases were considered mutants. The frequency in Michigan was about 1.8 x 10(-5) and the mutation rate about 4 x 10(-6) per gamete per generation. Affected persons may be visually handicapped because of nystagmus, cataract or glaucoma. The ratio of affected to normal among the offspring of an affected parent was 38 to 62, a significant difference from 50 to 50.
In an economically depressed area of eastern Canada, Gove et al. (1961) identified 77 cases of aniridia descended from an affected woman born in 1824. The aniridias showed approximately a 20% elevation of reproductive activity as compared with the rest of the community, and this community was in turn nearly twice as fertile as the rest of Canada.
Elsas et al. (1977) described a large pedigree in which visual acuity of affected members was nearly normal. By contrast, the presence of one or more of the associated ocular abnormalities--cataract, lens dislocation, foveal dysplasia, optic nerve hypoplasia, and nystagmus--contributes to severe reduction in visual acuity. About half of cases develop glaucoma which causes severe ocular pain and, if not treated successfully, can destroy residual vision.
Ferrell et al. (1980) studied a large kindred with aniridia in which they described marked phenotypic variability with many persons being unaware of the presence of the trait because they had round pupils and good vision in at least one eye. Thinning of the iris was a manifestation. Ferrell et al. (1980, 1987) erroneously mapped aniridia in this family to chromosome 2 (see MAPPING section). This error was in part due to diagnostic difficulties; diagnosis, especially at an early age, may be difficult in patients with round and central pupils. Both normal and affected irides of such at-risk family members transilluminate in early infancy and do not transilluminate at maturation. This is consistent with the hypothesis that aniridia is a disease of the neuroectoderm with normal acquisition of iris epithelial pigmentation and pupillary musculature, but secondary faulty induction of the 3 neural crest mesenchymal waves into the corneal endothelium and trabecular meshwork, corneal stroma, and iris stroma. The variability in phenotype and the resulting diagnostic difficulties were commented on by Shaw et al. (1960) and Hittner et al. (1980).
Glaser et al. (1994) reported a family segregating 2 different mutations in the PAX6 gene (see MOLECULAR GENETICS), in which the 3 affected individuals exhibited distinct ocular phenotypes. The mother had defects characteristic of aniridia, including essentially absent irides, bilateral cataracts, decreased visual acuity in both eyes, an irregular searching nystagmus, small corneal diameters, and foveal hypoplasia with extension of blood vessels through the central retinal region. She had no intellectual or neurologic impairment. Similar findings were present in her mother and half brother. The father had developed bilateral cataracts shortly after birth, which progressed and were extracted at ages 38 and 40. A circumferential corneal pannus was first noted at age 50. The irides had a large postsurgical defect but were otherwise normal, and the foveas appeared well developed. Their daughter, who was born by cesarean section at 43 weeks' gestation, had severe craniofacial and central nervous system defects and clinical anophthalmia, and died on the eighth day of life. The head was small with disproportionately large ears. The nose was malformed with a flattened bridge and pinpoint external nares. She also had choanal atresia. Postmortem examination confirmed complete agenesis of the eyes, periocular tissues, optic nerves, and chiasm. The brain was small and misshapen. The cerebral hemispheres were thin and widely separated with a single open ventricular system. Midline fusion occurred focally in the anterior septal area, but the corpus callosum was otherwise absent.
The mild extraocular phenotypes reported in the small eye mouse, including olfactory bulb hypoplasia, axon guidance defects, cortical plate hypocellularity, and decreased basal ganglia volume, indicate the possibility of subtle brain alterations in human heterozygotes. This prompted Sisodiya et al. (2001) to screen 14 subjects with aniridia for PAX6 mutations and to use MRI to look for alterations in brain structure. Olfactory capacity was also tested. Because PAX6 governs cellular proliferation and migration of 'later-born' neurons, and because subtle but significant malformation may be detectable only by quantitative MRI, they measured regional brain volumes. Interhemispheric communication is through 2 major pathways, the anterior commissure and the corpus callosum. To determine whether callosal hypoplasia, found in both homozygous small eye mice and the human compound heterozygote (Glaser et al., 1994), also occurs in human heterozygotes, Sisodiya et al. (2001) measured callosal area and found significant reduction in the study group compared with controls. Two subjects with hypoplastic olfactory bulbs had mild or moderate hyposmia. Of the remaining 12 subjects with visually normal olfactory bulbs, only 1 had normal olfaction. Some subjects were previously aware of notably reduced olfaction. The authors noted that anosmia had been reported anecdotally in an aniridia subject (Martha et al., 1995). Absence of the anterior commissure without callosal agenesis had not been reported as a malformative sequence in humans. In a similar study of 24 subjects with ocular abnormalities and PAX6 mutations, including the 14 patients reported by Sisodiya et al. (2001), Mitchell et al. (2003) found absence of the pineal gland in 13 subjects and absence of the AC in 12. The authors noted that neither of these findings had been reported in Pax6 mutant mouse models.
Because some of the sporadic cases of aniridia are caused by large chromosomal deletions, which may include the Wilms tumor gene (607102), such patients may have an increased risk of developing Wilms tumor (WT1; 607102). Based on the unique registration of both cancer and aniridia cases in Denmark, Gronskov et al. (2001) were able to make an accurate risk estimate for Wilms tumor in sporadic aniridia. They found that patients with sporadic aniridia had a relative risk of 67 (CI, 8.1-241) of developing Wilms tumor. Among patients investigated for mutations, Wilms tumor developed in only 2 patients of 5 in whom the Wilms tumor gene was deleted. None of the patients with smaller chromosomal deletions or intragenic mutations were found to develop Wilms tumor.
Recchia et al. (2002) reviewed the usefulness of optical coherence tomography (OCT) in the diagnosis of foveal hypoplasia, which may be seen in aniridia or oculocutaneous albinism (203100), as well as in other syndromes. In a patient with foveal hypoplasia (136520), OCT allowed detailed examination of the macular anatomy, showing preservation of multiple inner retinal layers where there should have been none, indicating that the fovea was thicker than normal. The authors suggested that a more accurate term would be 'foveal dysgenesis,' and proposed that OCT might prove helpful in the evaluation of patients with unexplained visual loss.
In 32 eyes of 17 patients with aniridia, Brandt et al. (2004) described markedly increased central corneal thickness: 631.6 +/- 50.8 microns versus 535 microns in normal controls. They suggested that increased central corneal thickness might lead to incorrect estimates of intraocular pressure by applanation techniques and highlighted the importance of monitoring aniridia patients for the development of glaucoma through regular gonioscopy and optic nerve examination.
Ticho et al. (2006) described a 6-year-old Caucasian boy with 'atypical Gillespie syndrome' (see 206700) and a de novo mutation in the PAX6 gene (see MOLECULAR GENETICS), who had partial aniridia, balance disorder, hand tremor, and learning disability. Eye findings included mild bilateral ptosis, exotropia, corectopia, decreased visual acuity, patchy temporal absence of the anterior iris leaflet, iris processes crossing the trabecular network, anterior lens capsule opacities, foveal hypoplasia, retinal vascular tortuosity, and retinal hypopigmentation. He had slight facial dysmorphism. He had received therapy for a mild balance disorder, low tone in his upper extremities, and rigidity in the lower extremities, and had been evaluated for mild psychomotor delay, which led to a diagnosis of attention deficit hyperactivity disorder and a central auditory processing delay. Brain MRI revealed no focal abnormalities, including absence of cerebellar findings. Although the ocular features and learning disorder were suggestive of Gillespie syndrome (see 206700), the authors stated that the novelty of the PAX6 mutation and relative subtlety of neurologic findings argued against that conclusion.
Graziano et al. (2007) described a 9.5-year-old girl, born of nonconsanguineous parents, who had aniridia, ataxia, and moderate mental retardation and was heterozygous for a de novo mutation in the PAX6 gene (see MOLECULAR GENETICS). Dysmorphic features included an asymmetric face with high forehead, ptosis, strabismus, hypertelorism, depressed nasal bridge with anteverted nostrils, high and narrow palate, folded ears with hypoplastic antihelix, arachnodactyly, and cervical, dorsal, and lumbar kyphosis. She had an ataxic gait, intention and action tremor of both upper limbs, axial hypotonia, and lower limb hypertonia. Ophthalmologic examination revealed clear cornea and lens and bilateral symmetric aniridia; the rudimentary iris stump was regular without tufts. Cerebral MRI at 6 months of age showed dilation of the left Sylvian fissure and normal myelinization; magnetic resonance spectroscopy at age 9.5 years was consistent with mild neurodegenerative alteration of the cerebellar area. Karyotyping at 6 years of age was normal. The authors noted that the patient lacked the festooned pupillary edge and tufting considered to be pathognomonic for Gillespie syndrome, and that she had other clinical manifestations that were atypical for Gillespie patients; they stated that the role of additional unknown genetic variants could not be excluded.
Solomon et al. (2009) reported a 4-year-old boy with prenatally diagnosed trisomy 21 who was also compound heterozygous for mutations in the PAX6 gene. He had extreme microcephaly, bilateral severe microphthalmia, choanal atresia, smooth philtrum, severe developmental delay, and renal dysplasia with recurrent urinary tract infections; evidence for hypopituitarism included central hypothyroidism, secondary adrenal insufficiency, and a history of cryptorchidism and micropenis, which had been treated with exogenous testosterone. He also had neonatal-onset insulin-dependent diabetes mellitus, but abdominal MRI showed no pancreatic anomalies. Structural abnormalities of the brain by MRI included agenesis of the corpus callosum, midline interhemispheric cyst, hypoplastic pons and vermis, possible Dandy-Walker malformation, dysplastic tectum, pituitary and hypothalamic hypoplasia, and a globular basal ganglia. His mother had bilateral aniridia, glaucoma, and corneal opacification, as well as a dense cataract in the right eye; she also had elevated fasting blood glucose, although she had not been diagnosed with diabetes. There was an extensive family history of autosomal dominant aniridia in her family: her sister, mother, maternal aunt and uncle, and maternal grandfather were all affected. The proband's father had a history of early childhood cataract and eventual blindness, as well as hearing loss. Examination revealed high palate and dental crowding; ophthalmologic examination showed microcornea, right cataract, and left aphakia, as well as subtle iris hypoplasia and corectopia. There was an extensive family history of cataract and hearing loss in his family, affecting 4 maternal aunts and 1 uncle as well as his maternal grandfather. The proband had a brother who had died in infancy, who was described as having very similar structural brain anomalies, clinical anophthalmia, and neonatal diabetes.
Collinson et al. (2001) suggested that partial therapeutic correction of the lens, presumably by gene therapy, in affected individuals identified by prenatal diagnosis (Churchill et al., 2000) could significantly ameliorate several of the clinical defects responsible for poor eye sight, ocular degeneration, and blindness.
Although initial visual acuity in individuals with aniridia may be 20/200 (legal blindness) due to macular hypoplasia, progressive visual loss may occur because of presenile cataract, secondary angle closure glaucoma, and aniridic keratopathy. Penetrating keratoplasty had not been effective in the long-term management of aniridic keratopathy because it failed to address the keratolimbal stem cell deficiency that caused the progressive corneal pannus and scarring. Holland et al. (2003) performed keratolimbal allograft prior to penetrating keratoplasty in a series of patients with aniridic keratopathy. The sequential surgeries improved mean visual acuity from 20/1000 to 20/165 and resulted in stable ocular surfaces in those patients receiving systemic postoperative immunosuppression. Topical immunosuppressants were found to be ineffective.
To treat the secondary angle closure glaucoma in patients with aniridia, Arroyave et al. (2003) reviewed outcomes of 8 eyes of 5 patients over an 11 year period. Mean preoperative intraocular pressure (IOP) was 35 mm Hg; mean postoperative IOP was 15 mm Hg. Final visual acuity improved in 63% of eyes, remained unchanged in 25%, and loss of light perception vision occurred in 1 eye due to a retinal detachment. Success rate was 100% at 6 months and 88% at 1 year. They concluded that glaucoma drainage device placement for glaucoma associated with aniridia achieved IOP control and vision reservation in most patients.
Approximately a third of all cases of aniridia are sporadic and these are often found to have cytogenetically detectable deletions involving 11p13, which, if extensive enough, cause the WAGR contiguous gene syndrome (194072)(Ton et al., 1991).
Simola et al. (1983, 1984) described a family with aniridia in 3 generations and an apparently balanced chromosomal translocation, t(4;11)(q22;p13). The 3 affected persons were otherwise clinically normal, had no signs of Wilms tumor, and had normal red cell catalase levels. Simola et al. (1983) suggested that aniridia in this family was caused by a submicroscopic deletion at the translocation breakpoint 11p13 or by a position effect on the same chromosome segment. The observations indicated that the loci for aniridia and Wilms tumor susceptibility are separate. Turleau et al. (1984) also suggested that the determinant of aniridia may be separate from that for nephroblastoma (Wilms tumor), on the basis of a boy with deletion of most of 11p13, low catalase, nephroblastoma, chordee and cryptorchidism but normal irides and no mental retardation. The authors pointed out that in all published cases with aniridia the distal half of 11p13 is deleted, whereas in the case they were reporting there was 'a tiny residual distal segment.' Moore et al. (1986) observed a kindred like that of Simola et al. (1983). Isolated aniridia was associated with an apparently balanced translocation, t(11;22)(p13;q12.2). Of the 11 affected persons in 5 generations, 8 who were studied karyologically had the translocation, whereas 4 unaffected persons had normal karyotypes. In 4 of the 8, aniridia was associated with glaucoma and cataracts. No Wilms tumor or genitourinary abnormalities were found in the family and restriction enzyme analysis showed no abnormality of the catalase gene. They reviewed data suggesting that the order is centromere--CAT--FSHB (136530)--Wilms tumor--pter.
From a review of many reported cases, Moore et al. (1986) concluded that single breaks are associated with isolated aniridia, whereas deletion of 11p13 results in the WAGR syndrome. The association of a disorder with seemingly balanced autosomal reciprocal translocation of several other types has been observed (see, for example, 101200, 115650, 127300, 157900, 175700, 182900, 268800).
Davis et al. (1988) identified 2 anonymous DNA segments from the WAGR region of 11p13. Both probes identified a cytologically undetectable deletion associated with a balanced chromosome translocation inherited by a patient with familial aniridia but not Wilms tumor. The same 2 DNA segments were also included in the distal 11p14.1-p13 deletion of another patient who had aniridia, Wilms tumor, and hypogonadism, but they were not included in the 11p13-p12 deletion of a third patient who had Wilms tumor but not aniridia. These 2 DNA segments, labeled D11S93 and D11S95, map between the catalase and FSH-beta loci, either very near to or within the aniridia gene. Gessler et al. (1989) studied 2 families in which familial aniridia was associated with chromosome translocations involving 11p13. In 1 kindred the translocation was associated with a deletion; probes for this region were used to identify and clone the breakpoints of the translocation in the second kindred. Comparison of phage restriction maps excluded the presence of any sizable deletion in this case. Sequences at the 11p13 breakpoint were found to be conserved in multiple species, suggesting that the translocation fell within the AN gene. Initial sequence analysis of the breakpoint showed that the translocation occurred within an open reading frame that was flanked by consensus splice donor and acceptor sites, suggesting that it may represent an exon. Pettenati et al. (1989) reported a fourth instance of a break at 11p13 in association with aniridia: a father and daughter with isolated aniridia were found to have an apparently balanced, reciprocal translocation involving chromosomes 5 and 11: t(5;11)(q13.1;p13). Fukushima et al. (1993) described familial aniridia associated with a cryptic inversion within 11p13.
Crolla and van Heyningen (2002) studied 77 patients with aniridia, referred for cytogenetic analysis predominantly to assess Wilms tumor risk, by FISH using a panel of cosmids encompassing the aniridia-associated PAX6 gene, the Wilms tumor predisposition gene WT1 (607102), and flanking markers in distal chromosome 11p13. Thirty patients were chromosomally abnormal. Cytogenetically visible interstitial deletions involving 11p13 were found in 13 patients, 11 of which included WT1. A further 13 patients had cryptic deletions detectable only by FISH, 3 of which included WT1. Six of these, with deletions less than 500 kb, shared a similar proximal breakpoint within a cosmid containing the last 10 exons of PAX6 and part of the neighboring gene, ELP4 (606985). Two of these 6 patients were mosaic for the deletion. The remaining 4 patients had chromosomal rearrangements. The proportion and spectrum of chromosome anomalies in 4 of 14 (28.5%) familial and 26 of 63 (41%) sporadic cases were not significantly different. An unexpectedly high frequency of chromosomal rearrangements was associated with both sporadic and familial aniridia in this cohort.
In a large family segregating aniridia, Ferrell et al. (1980, 1987) found linkage of the disorder to the ACP1 locus (171500) on chromosome 2p. However, Lyons et al. (1992) updated and expanded this kindred and excluded linkage to ACP1 (up to theta = 0.17 with lod = -2) as well as to other 2p markers. They found evidence of linkage to 11p13. The PvuII RFLP at the D11S323 locus showed no recombinants with a maximum lod score of 6.97 at theta = 0.00.
Mannens et al. (1989) found close linkage between autosomal dominant aniridia and the CAT locus (115500) on 11p13; maximum lod = 7.27 at theta = 0.00. In the large Dutch family they studied, they excluded linkage between aniridia and the marker at 2p25 linked to ACP1.
An aniridia locus mapped to chromosome 2 was designated AN1, and a locus mapped to chromosome 11p13 was designated AN2. Because the mapping to chromosome 2 was disproved, the AN2 locus is now designated AN1.
Fantes et al. (1992) described a mother and son with aniridia associated with a submicroscopic 11p13 deletion. This was a rare case of an inherited WAGR deletion; the family was ascertained through the son who presented with Wilms tumor in a horseshoe kidney. Using fluorescence in situ hybridization (FISH) in cell lines from patients with aniridia, Fantes et al. (1992) found that the candidate aniridia gene is deleted, supporting the murine Pax6 homolog as a strong candidate for the AN gene.
Jordan et al. (1992) analyzed the PAX6 gene in cell lines from 2 cases of sporadic aniridia and identified a 2-bp insertion (607108.0001) in one and deletion of an exon (607108.0002) in the other.
Hanson et al. (1993) described 4 point mutations in the PAX6 gene (607108) in aniridia patients, both sporadic and familial. They suggested that the frequency at which PAX6 mutations are found is an indication that lesions in PAX6 account for most cases of aniridia.
Glaser et al. (1994) analyzed the PAX6 gene in a family with 3 distinct ocular phenotypes and identified 2 different mutations: the mother, who had aniridia, was heterozygous for an R103X mutation (607108.0005), whereas the father, who had congenital cataracts and late-onset corneal dystrophy, was heterozygous for an S353X mutation (607108.0006). Their severely affected daughter, who had microcephaly, choanal atresia, and bilateral anophthalmia, was compound heterozygous for both mutations.
Martha et al. (1995) found 4 different mutations in PAX6 in 1 sporadic and 5 familial cases of aniridia: a previously reported mutation and 3 novel ones. In a family with an affected 32-year-old woman and a 10-year-old daughter, the mother had bilateral erosion of the cornea and blood vessels on the corneas with bilateral cataracts and also had very thin irides (see 607108.0008). In another family with affected father and son, the father had aniridia, glaucoma, cataracts, and macular agenesis (see 607108.0009). In yet another family with affected mother and daughter, the mother but not the daughter also had anosmia (see 607108.0010). In all 6 of the aniridia cases, the mutations were predicted to generate incomplete PAX6 proteins and supported the theory that aniridia is caused by haploinsufficiency of PAX6.
Axton et al. (1997) screened DNA from 12 aniridia patients for PAX6 mutations and found a total of 10 mutations from 5 familial and 5 sporadic cases. Mutations were not found in the DNA from 2 patients without a family history. All 10 mutations found resulted in functional haploinsufficiency.
Prosser and van Heyningen (1998) reviewed PAX6 mutations. They commented that no locus other than 11p13 has been implicated in aniridia and that PAX6 is clearly the major, if not the only, gene responsible. Prosser and van Heyningen (1998) commented that in a gene with such extraordinarily high sequence conservation throughout evolution, there should be undiscovered missense mutations. These might be associated with unidentified phenotypes. They pointed out that olfactory system anomalies, cerebellar coordination problems, or pancreatic malfunction might be expected and that some mild mutations might give rise to a viable recessive phenotype, most likely in consanguineous families.
In a mother and 2 sons who had aniridia, ptosis, and slight to moderate mental retardation, Malandrini et al. (2001) identified a missense mutation in the PAX6 gene (S119R; 607108.0023). The sons also had horizontal nystagmus, behavioral changes, and diffuse hypotonia. Brain MRI in all 3 patients were normal. The authors suggested that the missense mutation was responsible for both aniridia and ptosis, and possibly also for the observed cognitive dysfunction in this family.
In a boy with partial aniridia of the left eye presenting as a pseudocoloboma, Morrison et al. (2002) identified heterozygosity for a missense mutation in the PAX6 homeodomain (R242T; 607108.0022). There was no family history of congenital eye malformation. The right eye of the patient was completely normal, and the mutation was subsequently identified in blood DNA from his phenotypically normal mother, suggesting low penetrance. Molecular analysis by D'Elia et al. (2006) revealed that the DNA-binding properties of the R242T homeodomain and the paired domain were not altered; however, the mutation reduced sensitivity to trypsin digestion, resulting in increased mutant protein levels. D'Elia et al. (2006) suggested that the R242T phenotype could be due to abnormal increase of PAX6 protein, in keeping with the reported sensitivity of the eye phenotype to increased PAX6 dosage (Schedl et al., 1996).
In a 6-year-old Caucasian boy with partial aniridia, mild balance disorder, hand tremor, and learning disability, Ticho et al. (2006) identified a splice site mutation in the PAX6 gene (607108.0024).
In a 9.5-year-old girl with aniridia, ataxia, and moderate mental retardation, Graziano et al. (2007) identified heterozygosity for a nonsense mutation in the PAX6 gene (607108.0025). The authors noted that it was difficult to evaluate the real prevalence of mental deficits in patients with PAX6 mutations because the focus of most investigations was on eye phenotypes; they also stated that the role of additional unknown genetic variants in this patient could not be excluded.
Atchaneeyasakul et al. (2006) described the ophthalmic findings and mutation analyses of the PAX6 gene in 10 Thai aniridia patients from 6 unrelated families. Seven patients developed cataracts and 6 patients developed glaucoma. Mutation analysis demonstrated 4 different truncating mutations, 2 of which were de novo. All mutations resulted in loss of function of the PAX6 protein. Atchaneeyasakul et al. (2006) concluded that their data confirmed inter- and intrafamilial variable phenotypic manifestations of which the underlying mechanisms might be haploinsufficiency or dominant-negative mutations.
In a girl with aniridia, microphthalmia, microcephaly, and cafe-au-lait macules, Henderson et al. (2007) identified heterozygous mutations in the PAX6 (R38W; 607108.0026), NF1 (R192X; 613113.0046), and OTX2 (Y179X; 600037.0004) genes. Her mother, who carried the NF1 and PAX6 mutations, had neurofibromatosis type I (NF1; 162200) with the typical eye defects of retinal fibroma, optic nerve glioma, and gross Lisch nodules on the iris; in addition, although her eyes were of normal size, she had small corneas, as well as cataracts, optic nerve hypoplasia, nystagmus, and mild iris stromal hypoplasia with normal-sized pupils. The proband's father, who had previously been studied by Ragge et al. (2005) and was heterozygous for the OTX2 nonsense mutation, had initially been diagnosed with Leber congenital amaurosis (LCA; see 204000), but also had features atypical of LCA, including bilateral mild microphthalmia, mild microcornea, and iridocorneal synechiae (see MCOPS5, 610125). Henderson et al. (2007) noted that the proband's phenotype was surprisingly mild, given that mutations in PAX6, OTX2, or NF1 can cause a variety of severe developmental defects.
Lyon (1988) suggested that 'small eye' (Sey) in the mouse, which is on chromosome 2, may be homologous to aniridia-2 inasmuch as there is a region of conserved homology of synteny between human 11p and mouse chromosome 2. This suggestion was corroborated by van der Meer-de Jong et al. (1990) who found through interspecies backcrosses for linkage mapping that the Sey gene lies between Fshb and Cas-1. In the human, AN2 lies between the 2 cognate genes, FSHB and CAT. Glaser et al. (1990) studied the Sey mutation by localizing in an interspecies backcross between Mus musculus/domesticus and Mus spretus, the region on mouse chromosome 2 carrying 9 evolutionarily conserved DNA clones from proximal human 11p. In Dickie's small eye, they found deletion of 3 clones that encompass the aniridia and Wilms tumor susceptibility genes in man. Unlike their human counterparts, the heterozygous Dickie's small eye mice do not develop nephroblastomas. The homology of Sey and AN2 was established by the cloning of the AN2 gene in the human and its homolog in the mouse, and the demonstration of mutations in 3 independent Sey alleles (Hill et al., 1991). The mutations would predictably disrupt the function of the gene, which belongs to the Pax multigene family. This family of developmental genes was first described in Drosophila. A Pax gene referred to as Pax6 is identical to the mouse homolog of the candidate aniridia gene. Matsuo et al. (1993) found an internal deletion of about 600 bp in the Pax6 gene in rats homozygous for the small eye mutation. Deletion was due to a single base insertion that generated an abnormal 5-prime donor splice site. They showed that anterior midbrain crest cells in the homozygous embryos reached the eye rudiments but did not migrate any further to the nasal rudiments, suggesting that the Pax6 gene is involved in conducting migration of neural crest cells from the anterior midbrain.
Quiring et al. (1994) isolated a Drosophila gene that contains both a paired box and a homeobox and has extensive sequence homology to the mouse Pax6 gene that is mutant in small eye. They found that the Drosophila gene mapped to chromosome IV in a region close to the 'eyeless' locus (ey). Two spontaneous mutations contained transposable element insertions into the cloned gene and affected gene expression, particularly in the eye primordia, thus establishing that the cloned gene encodes 'ey.' The finding that ey of Drosophila, small eye of the mouse, and human aniridia are encoded by homologous genes suggests that eye morphogenesis is under similar genetic control in both vertebrates and insects, in spite of the large differences in eye morphology and mode of development. Zuker (1994) noted that in his book 'On the Origin of Species,' Darwin dealt with the difficulties in explaining the evolution of organs of extreme perfection and complication and focused on the eye. Furthermore, Salvini-Plawen and Mayr (1977), in their study of the evolution of eyes, commented: 'It requires little persuasion to become convinced that the lens eye of a vertebrate and the compound eye of an insect are independent evolutionary developments.' The Drosophila compound eye is composed of 800 facets or ommatidia, each containing photoreceptor neurons, accessory cells, and a lens.
Schedl et al. (1996) generated YAC transgenic mice carrying the human PAX6 locus. When crossed onto the small eye background, the transgene rescued the mutant phenotype. Strikingly, mice carrying multiple copies on a wildtype background showed specific developmental abnormalities of the eye, but not of other tissues expressing the gene. Schedl et al. (1996) commented on the occurrence of abnormalities of the eye in patients with duplication of part of chromosome 11 including the PAX6 locus. The fact that simple overexpression of the human gene in transgenic mice causes abnormalities is encouraging for the generation of mouse models for human trisomies. They noted that generation of transgenics carrying large fragments of DNA should make it possible to narrow it down and identify genes responsible for particular aspects of trisomic phenotypes.
Collinson et al. (2001) described lens defects in heterozygous small eye mice and autonomous deficiencies of heterozygous Pax6 +/- cells in the developing lens of chimeric wildtype/heterozygous chimeras. They identified 2 separate defects of the lens by analyzing the distribution of heterozygous cells in chimeras: heterozygous mutant cells were less readily incorporated into the lens placode than wildtype, and those that were incorporated into the lens were not maintained efficiently in the proliferating lens epithelium. The lens of chimeric eyes is, therefore, predominantly wildtype from embryonic day 16.5 onward, whereas heterozygous cells contribute normally to all other eye tissues. Eye size and defects of the iris and cornea were corrected in fetal and adult chimeras with up to 80% mutant cells. These aspects of the phenotype may be secondary consequences of primary defects in the lens and, therefore, may have clinical relevance for the human aniridia (PAX6 +/-) phenotype.
Ramaesh et al. (2003) found that the corneal abnormalities in heterozygous Pax6 +/- small eye mice were similar to those in aniridia-related keratopathy in PAX6 heterozygous patients. The mice showed incursion of goblet cells, suggesting impaired function of Pax6 +/- limbal stem cells; abnormal expression of cytokeratin-12 (601687), which might result in greater epithelial fragility; and age-related corneal degeneration, which might reflect poor wound-healing responses to accumulated environmental insults. Ramaesh et al. (2003) suggested that these findings extended the relevance of this mouse model of human aniridia to include corneal abnormalities.
Ramaesh et al. (2006) tested whether the Pax6 +/- genotype affected corneal wound-healing responses, including stromal cell apoptosis, epithelial cell migration rate, and matrix metalloproteinase-9 (MMP9; 120361) secretion, in culture. They concluded that the cumulative effects of abnormal wound-healing responses, characterized by increased stromal cell apoptosis and reduced levels of MMP9 secretion, might contribute to the corneal changes in the Pax6 +/- mice.
Li et al. (2007) created and examined Pax6 mutant mouse chimeras from postnatal day (P) 0 to P10. They found that Sey/Sey retinal neurons did not survive past birth. A small population of Pax6-null cells was found in the retina that contributed to the blood vessel-associated cells that have their origins outside the retina. Furthermore, in contrast to previous reports, Sey/+ cells did contribute to the lens epithelium and Sey/Sey cells did not contribute to the anterior retinal pigment epithelium.
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