PAX6 Mutation as a Genetic Factor Common to Aniridia and Glucose Intolerance

Abstract

A paired homeodomain transcription factor, PAX6, is a well-known regulator of eye development, and its heterozygous mutations in humans cause congenital eye anomalies such as aniridia. Because it was recently shown that PAX6 also plays an indispensable role in islet cell development, a PAX6 gene mutation in humans may lead to a defect of the endocrine pancreas. Whereas heterozygous mutations in islet-cell transcription factors such as IPF1/IDX-1/STF-1/PDX-1 and NEUROD1/ BETA2 serve as a genetic cause of diabetes or glucose intolerance, we investigated the possibility of PAX6 gene mutations being a genetic factor common to aniridia and diabetes. In five aniridia and one Peters' anomaly patients, all of the coding exons and their flanking exon-intron junctions of the PAX6 gene were surveyed for mutations. The results of direct DNA sequencing revealed three different mutations in four aniridia patients: one previously reported type of mutation and two unreported types. In agreement with polypeptide truncation and a lack of the carboxylterminal transactivation domain in all of the mutated PAX6 proteins, no transcriptional activity was found in the reporter gene analyses. Oral glucose tolerance tests revealed that all of the patients with a PAX6 gene mutation had glucose intolerance characterized by impaired insulin secretion. Although we did not detect a mutation within the characterized portion of the PAX6 gene in one of the five aniridia patients, diabetes was cosegregated with aniridia in her family, and a single nucleotide polymorphism in intron 9 of the PAX6 gene was correlated with the disorders, suggesting that a mutation, possibly located in an uncharacterized portion of the PAX6 gene, can explain both diabetes and aniridia in this family. In contrast, the patient with Peters' anomaly, for which a PAX6 gene mutation is a relatively rare cause, showed normal glucose tolerance (NGT) and did not show a Pax6 gene mutation. Taken together, our present observations suggest that heterozygous mutations in the PAX6 gene can induce eye anomaly and glucose intolerance in individuals harboring these mutations. Diabetes 51:224 -230, 2002

A common variant upstream of the PAX6 gene influences islet function in man

“…The similarity of effects in vivo and in vitro in human islets provides strong support for the central role of PAX6 in development of islet function and regulation of glucose metabolism. The finding that low PAX6 expression causes impaired insulin secretion and affects glucose metabolism is in line with previously published findings in both animal models and human families with protein-altering mutations in the PAX6 gene [4][5][6][7]. However, these studies were performed in individuals with more severe mutations making generalisation of the findings to potential effects of common variants in the gene difficult.…”

“…There have been several reports of PAX6 mutation carriers having abnormal glucose tolerance, and of type 2 diabetes co-segregating with aniridia in families with PAX6 mutations [4][5][6]. Recently, Wen et al reported that carriers of a PAX6 R240Stop mutation developed impaired glucose tolerance and/or diabetes with age [6].…”

Conserved role for the Dachshund protein with Drosophila Pax6 homolog Eyeless in insulin expression

“…In mammals, the production and secretion of insulin and glucagon from the pancreas are crucial for glucose homeostasis. Mutations in the Pax6 locus cause impaired insulin secretion, early-onset diabetes mellitus, and aniridia (16,32,33). A recent genome-wide in silico promoter analysis identified Glucagon and Igf2 as potential targets of mammalian Dach1 (34).…”

Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes

“…Because GATA-4 is known to be expressed in cells of the cardiovascular system (34,35), this promoter polymorphism may induce changes in Bmal1 expression in key organs involved in blood pressure regulation. In addition, as Pax6 expression is positively regulated by Clock and Bmal1 (36), reduced Bmal1 transcription in SHR may result in decreased expression of Pax6, which may in turn fail to compensate GATA-4-mediated Bmal1 expression down-regulation and directly affect glucose homeostasis (17,37). We have verified the full sequence conservation in SHR and WKY of other components of the molecular clock, Per1 (data not shown) and Clock (38), which are unlikely to alter allele specific biological effects of Bmal1 variants.…”