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Abstract #18535 Published in IGR 3-3
PAX6 mutation as a genetic factor common to aniridia and glucose intolerance
Yasuda T; Kajimoto Y; Fujitani Y; Watada H; Yamamoto S; Watarai T; Umayahara Y; Matsuhisa M; Gorogawa Si S; Kuwayama YDiabetes 2002; 51: 224-230
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. While 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, the authors 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 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 carboxyl-terminal transactivation domain in all the mutated PAX6 proteins, no transcriptional activity was found in the reporter gene analyses. Oral glucose tolerance tests revealed that all the patients with a PAX6 gene mutation had glucose intolerance characterized by impaired insulin secretion. Although no mutation was detected within the characterized portion of the PAX6 gene in one of the five aniridia patients, diabetes was co-segregated 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, the present observations suggest that heterozygous mutations in the PAX6 gene can induce eye anomaly and glucose intolerance in individuals harboring these mutations.
Dr T. Yasuda, Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan
Classification:
1.2 Population genetics (Part of: 1 General aspects)
