PAX6 and Congenital Eye Malformations

Abstract

The PAX6 gene is a paradigm for our understanding of the molecular genetics of mammalian eye development. Twelve years after its identification it is one of the most intensively studied genes, both in terms of its diverse and complex functions during oculogenesis and its role in an ever-increasing variety of human congenital eye malformations. The PAX6 field has benefited greatly from the continued input of clinicians, human geneticists and developmental biologists. This review summarizes the latest data on the PAX6 mutation spectrum and recent PAX6 was identified as a candidate aniridia gene during the search for the genes responsible for the WAGR syndrome (Wilms tumor, aniridia, genitourinary malformations, and mental retardation), which is caused by hemizygous deletions of 11p13 (1). Heterozygous intragenic mutations were subsequently described in many nonsyndromic aniridia cases, confirming PAX6 as the aniridia gene (2-5). At the same time Pax6 mutations were found in the classical mouse microphthalmia mutant small eye (6).The PAX6 protein is a transcriptional regulator with two highly conserved DNA binding domains, a paired domain and a homeodomain (1, 3, 7, 8; Fig. 1). The homeodomain is followed by a proline, serine, and threonine-rich transactivation domain (9). The last 30 amino acids constitute a highly conserved C-terminal peptide that modulates DNA binding by the homeodomain (10). THE SPECTRUM OF HUMAN PAX6 MUTATIONSMolecular analyses of WAGR syndrome cases showed that aniridia can be caused by deletion of one copy of PAX6 (1, 11).

Pax6 3′ deletion results in aniridia, autism and mental retardation

“…Aniridia is almost exclusively caused by PAX6 mutations, which include nonsense (37%); frame shift (23%); and splice site, missense, anti-termination mutations, and in-frame deletions or insertions (39%) (Hanson 2003). Nonsense mutations are presumed to produce truncated transcripts that activate NMD, resulting in haploinsffiency of PAX6.…”

“…For example, while most PAX6 nonsense mutations lead to aniridia (MIM 106210), many missense mutations result in Peter's anomaly (MIM 603807) (Azuma et al 1996Azuma et al (1999). It is thought that while nonsense mutations result in haploinsufficiency due to nonsense mediated decay (NMD), missense mutations may affect the ability of Pax6 to bind to specific targets thereby leading to differing phenotypes (Azuma et al 2003;Chao et al (2003;Hanson (2003).…”

Molecular and developmental mechanisms of anterior segment dysgenesis

“…[5][6][7] The genes FOXC1 and PAX6 at 6p25, and 11p13 respectively have been identified, 8,9 but the others remain elusive. Nonetheless, these and other studies have firmly established the fact that is ASD genetically heterogeneous (Table 1); more than one gene causes the 10 but now known to underlie a range of other ocular conditions 11 including Peters anomaly and a rare case of ARS. 7,12,13 As well as causing ARS, PITX2, and FOXC1 mutations have been demonstrated in cases of Peters anomaly and primary congenital glaucoma (PCG).…”

Molecular analysis of a human PAX6 homeobox mutant

“…Therefore, it has been hypothesized that HD missense mutations induce stronger deleterious phenotypes than other PAX6 missense mutations. 19 Other missense mutations not yet examined probably exist in association with other phenotypes distinct from aniridia, in view of the broad expression pattern of PAX6 gene. An alternative hypothesis is that most part of HD mutations would have no phenotypic effect on eye.…”

“…As the Pax6 HD is extremely conserved throughout evolution, it has been proposed that missense mutations of the HD may severely disrupt development causing more deleterious phenotypes than those due to mutations in the PD. 19 Among human PAX6 homeobox mutations, R242T was identified in a male child with partial aniridia in the left eye, presenting as a pseudo-coloboma. 20 The arginine at position 242 of the Pax6 protein is highly conserved through vertebrate evolution.…”