{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T17:06:12Z","timestamp":1791133572857,"version":"4.1.0"},"reference-count":33,"publisher":"American Diabetes Association","issue":"1","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,1,1]]},"abstract":"<jats:p>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\u2019 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\u2019 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.<\/jats:p>","DOI":"10.2337\/diabetes.51.1.224","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"224-230","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":131,"title":["<i>PAX6<\/i> Mutation as a Genetic Factor Common to Aniridia and Glucose Intolerance"],"prefix":"10.2337","volume":"51","author":[{"given":"Tetsuyuki","family":"Yasuda","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitaka","family":"Kajimoto","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshio","family":"Fujitani","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotaka","family":"Watada","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuji","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Science, Osaka University Graduate School of Medicine, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Watarai","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Osaka Kouseinenkin Hospital, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Umayahara","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munehide","family":"Matsuhisa","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-ichi","family":"Gorogawa","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuaki","family":"Kuwayama","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Osaka Kouseinenkin Hospital, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuo","family":"Tano","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Science, Osaka University Graduate School of Medicine, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshimitsu","family":"Yamasaki","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatsugu","family":"Hori","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031216163827700_R1","doi-asserted-by":"crossref","unstructured":"Stoffers DA, Ferrer J, Clarke WL, Habener JF: Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Gent\u200817: 138\u2013139, 1997","DOI":"10.1038\/ng1097-138"},{"key":"2022031216163827700_R2","doi-asserted-by":"crossref","unstructured":"Melecki MT, Jhala US, Antonellis A, Fields L, Doria A, Orban T, Saad M, Warram JH, Montminy M, Krolewski AS: Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat Genet\u200823:323\u2013328, 1999","DOI":"10.1038\/15500"},{"key":"2022031216163827700_R3","doi-asserted-by":"crossref","unstructured":"St-Onge L, Sosa-Pineda B, Chowdhury K, Mansouri A, Gruss P: Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. Nature\u2008387:406\u2013409, 1997","DOI":"10.1038\/387406a0"},{"key":"2022031216163827700_R4","doi-asserted-by":"crossref","unstructured":"Sander M, Neubuser A, Kalamaras J, Ee HC, Martin GR, German MS: Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development. 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