title: 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 carboxyl-terminal 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.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Tetsuyuki
authors.initials: T
authors.lastname: Yasuda
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kajimoto
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujitani
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Watada
authors.forename: Shuji
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Takao
authors.initials: T
authors.lastname: Watarai
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Umayahara
authors.forename: Munehide
authors.initials: M
authors.lastname: Matsuhisa
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Gorogawa
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Kuwayama
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Tano
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D015783:Aniridia / Q000097:blood / Q000235:genetics*; D044466:Asian People; D001786:Blood Glucose / Q000378:metabolism; D002648:Child; D005091:Exons; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D018149:Glucose Intolerance / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D007564:Japan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D010375:Pedigree; D012097:Repressor Proteins / Q000235:genetics; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics
chemical_list: D001786:Blood Glucose; D005136:Eye Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors