The PAX6 (Paired Box 6) gene, a member of the paired box gene family, is located on the short arm of chromosome 11, where it spans a length of more than 22 kb. The entire gene is made up of 14 exons, including an alternatively splicing exon 5a, and generates three transcript isoforms by alternative splicing. The protein coded for by the gene is a transcription factor involved in several development pathways and expressed early in the development of the eye, numerous regions of the brain, and the pancreas. The protein contains three domains; a paired domain (PD) in the N-terminus, a proline-serine-threonine (PST) transregulatory domain in the C-terminus and a homeodomain (HD) separated by a glycine-rich linker sequence in the middle.
PAX6 has been isolated as a candidate gene for Congenital Aniridia, an ocular disorder characterized by partial or complete absence of the iris. Heterozygous mutations are found in about 40-80% of all non-syndromic aniridia patients. Causal mutations in the PAX6 gene are also found in other disorders of the eye, including cataract with late onset corneal dystrophy, coloboma of optic nerve, foveal hyperplasia, keratitis, morning glory disc anomaly, and Gillespie syndrome.
To date, more than 700 mutations have been reported in the PAX6 gene. Most of these mutations are located in exons 5-14, and are associated with defective eye development. The vast majority of these mutations are premature termination (nonsense) mutations, amino acid substitutions (missense), frameshifting or in-frame indels, and C-terminal extensions. Not surprisingly, it has been noticed that patients with missense mutations have the mildest phenotypes with better preserved iris structures. A small numbers of aniridia cases can be due to large chromosomal deletions or rearrangements involving the PAX6 locus.
Abouzeid et al. (2009) studied 10 patients with aniridia from three families of Egyptian origin and were able to identify two novel (c.170-174delTGGGC [p.L57fs17] and c.475delC [p.R159fs47]) and one known (c.718C>T [p.R240X]) PAX6 mutations in the affected members of the three families. Severe hypoplasia of the brain anterior commissure was associated with the p.L57fs17 mutation, absence of the posterior commissure with p.R159fs47, and optic chiasma atrophy and almost complete agenesis of the corpus callosum with p.R240X.
Al Nassar et al. (1996) described a 2.5-year old female with bilateral aniridia together with some dysmorphic features. Sequencing of exon 10 of the PAX6 gene did not reveal any mutation. However, the patient was found to have a de novo balanced translocation t[6;18] [q16;q23].
Khan and Aldahmesh (2008) reported two unrelated Saudi Arabian families with aniridia, which was confirmed by ophthalmic examination and PAX6 gene sequencing. The pedigrees of both families suggested dominant (or pseudodominant) inheritance of the classic aniridia phenotype. The affected individuals in the first family were heterozygous for a novel frameshift PAX6 mutation (c.delA1294). The unaffected mother in this family did not carry this mutation. The affected individuals in the second family had heterozygosity for a commonly-reported PAX6 nonsense mutation (c.1195C>T; p.Arg240X). Again, the unaffected mother who was tested did not carry this mutation. Khan and Aldahmesh (2008) concluded that PAX6 haploinsufficiency was likely to be the leading cause of classic familial aniridia in the Arabia Peninsula. In a subsequent study to determine the genetic and genomic alterations underlying classic aniridia in Saudi Arabia, Khan et al. (2011) conducted a prospective study of consecutive patients referred to a pediatric ophthalmologist (2005-2009). All 12 probands (4 months-25 years of age; four boys and eight girls) were products of consanguineous unions except for three, one of which was endogamous. Heterozygous PAX6 mutations (including two novel mutations) were detectable in all but two cases, both of which were sporadic. In one of these two cases, the phenotype segregated with homozygosity for a previously-reported pathogenic missense FOXC1 variant (p.P297S) when homozygosity for chromosome 11q24.2 deletion (chr11:125,001,547-125,215,177 [rs114259885; rs112291840]) was also present. In the other, no genetic or genomic abnormalities were found.
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