Human patients with aniridia caused by heterozygous PAX6 mutations display abnormal glucose metabolism, but the underlying molecular mechanism is largely unknown. Disturbed islet architecture has been proposed as the reason why mice with complete inactivation of paired box 6 (PAX6) in the pancreas develop diabetes. This is not, however, the case in human aniridia patients with heterozygous PAX6 deficiency and no apparent defects in pancreatic development. We investigated the molecular mechanism underlying the development of abnormal glucose metabolism in these patients.

A human aniridia pedigree with a PAX6 R240Stop mutation was examined for abnormal glucose metabolism using an OGTT. The underlying mechanism was further investigated using Pax6 R266Stop mutant small-eye mice, which also have abnormal glucose metabolism similar to that in PAX6 R240Stop mutation human aniridia patients.

Paired box 6 (PAX6) deficiency, both in aniridia patients with a heterozygous PAX6 R240Stop mutation and in mice with a heterozygous Pax6 R266Stop mutation, causes defective proinsulin processing and abnormal glucose metabolism. PAX6 can bind to the promoter and directly upregulate production of prohormone convertase (PC)1/3, an enzyme essential for conversion of proinsulin to insulin. Pax6 mutations lead to PC1/3 deficiency, resulting in defective proinsulin processing and abnormal glucose metabolism.

This study indicates a novel function for PAX6 in the regulation of proinsulin processing and glucose metabolism via modulation of PC1/3 production. It also provides an insight into the abnormal glucose metabolism caused by heterozygous PAX6 mutations in humans and mice.