The PAX6 protein, expressed by the PAX6 gene in humans, is a transcription factor necessary for the development of the eye, parts of the central nervous system,and crucial parts of the endocrine system including the pituitary gland, pineal gland, and pancreas [1]. It is a member of a family of highly conserved transcription factors found across a wide range of species including humans, mice, zebrafish, and many others[2].
Function
[3] and is largely localized in tissues of the developing and mature eye, where it catalyzes the transcription of many key genes necessary for the proper development of the eye. This includes key structural proteins in areas such as the crystallins[4], whose presence or absence are integral to the proper structure and opacity of the lens throughout the various stages of eye development maintenance of lens homeostasis[5], as well as triggering the differentiation of retinal stem cells associated with proper development and maintenance of the retinal structures[4]. PAX6 expression is also implicated in the proper development of the endocrine system, including the development of the pancreas and proper secretion of hormones responsible for the maintenance of proper blood sugar levels[4].
Disease
Mutations in the PAX6 gene are implicated in several diseases in humans, including congenital aniridia both as a standalone disease and also as a part of WAGR syndrome (Wilms tumor, Aniridia, Genitourinary anomalies, and mental Retardation syndrome[6]. Inheritance of mutations in the PAX6 gene happens in an autosomal dominant fashion<refname="recdev" />, resulting in haploinsufficiency where one copy of the chromosome bearing the PAX6 carries a version bearing a loss-of-function mutation[7].
While all of the previously mentioned diseases are a result of this PAX6 haploinsufficiency, PAX6 aniridia syndrome, more commonly known to the general public as aniridia, is the primary manifestation[8]. While the hallmark of aniridia is the patient either lacking an iris or possessing a rudimentary stump of an iris, the disease bears a high incidence of panocular manifestations such as foveal hypoplasia and the underdevelopment of the optic nerve, which can lead to photophobia and poor vision from an early age[7]. Aniridia patients are also prone to high incidences of glaucoma, corneal keratopathy (fibrosis of the cornea, often as a result of limbal stem cell deficiency, and premature development of cataracts[4], all of which lead to patients with aniridia needing a lifetime of specialized care from an ophthalmologist.
Relevance
The significant prevalence of fibrotic diseases such as corneal keratopathy and the premature formation of cataracts as a result of deficiencies in PAX6 and its highly conserved nature allows for research into the molecular mechanisms behind the formation of fibrotic tissue. Any understanding behind the mechanisms of the expression of PAX6 and the link between PAX6 expression and said disorders may be capable of leading to findings that may translate to applications to ameliorate the effects of cataracts and secondary cataracts (posterior capsular opacification) in the general population.
Structural highlights
The C-terminal domain of
The between the N-terminal and C-terminal domains of PAX6 consists of 15 residues and binds with the sugar phosphate backbone in the minor groove of the DNA being transcribed[3].
