|
 |
|
|||||||
|
|||||||||
© 2002 by the American Diabetes Association, Inc.
PAX6 Mutation as a Genetic Factor Common to Aniridia and Glucose Intolerance
1 Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan
2 Department of Ophthalmology and Visual Science, Osaka University Graduate School of Medicine, Suita, Japan
3 Department of Internal Medicine, Osaka Kouseinenkin Hospital, Osaka, Japan
4 Department of Ophthalmology, Osaka Kouseinenkin Hospital, Osaka, Japan
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.
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  P. Y. Woon, P. J. Kaisaki, J. Braganca, M.-T. Bihoreau, J. C. Levy, M. Farrall, and D. Gauguier Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes PNAS, September 4, 2007; 104(36): 14412 - 14417. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Lu, X. He, and S. Zhong Cross-species microarray analysis with the OSCAR system suggests an INSR->Pax6->NQO1 neuro-protective pathway in aging and Alzheimer's disease Nucleic Acids Res., July 13, 2007; 35(suppl_2): W105 - W114. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E Cerf Transcription factors regulating {beta}-cell function. Eur. J. Endocrinol., November 1, 2006; 155(5): 671 - 679. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Raum, K. Gerrish, I. Artner, E. Henderson, M. Guo, L. Sussel, J. C. Schisler, C. B. Newgard, and R. Stein FoxA2, Nkx2.2, and PDX-1 Regulate Islet {beta}-Cell-Specific mafA Expression through Conserved Sequences Located between Base Pairs -8118 and -7750 Upstream from the Transcription Start Site Mol. Cell. Biol., August 1, 2006; 26(15): 5735 - 5743. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Artner, J. Le Lay, Y. Hang, L. Elghazi, J. C. Schisler, E. Henderson, B. Sosa-Pineda, and R. Stein MafB: An Activator of the Glucagon Gene Expressed in Developing Islet {alpha}- and {beta}-Cells Diabetes, February 1, 2006; 55(2): 297 - 304. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. V. Fischbach, K. L. Trout, J. Lewis, C. A. Luis, and M. Sika WAGR Syndrome: A Clinical Review of 54 Cases Pediatrics, October 1, 2005; 116(4): 984 - 988. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Davis-Silberman, T. Kalich, V. Oron-Karni, T. Marquardt, M. Kroeber, E. R. Tamm, and R. Ashery-Padan Genetic dissection of Pax6 dosage requirements in the developing mouse eye Hum. Mol. Genet., August 1, 2005; 14(15): 2265 - 2276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Zhao, M. Guo, T.-a. Matsuoka, D. K. Hagman, S. D. Parazzoli, V. Poitout, and R. Stein The Islet {beta} Cell-enriched MafA Activator Is a Key Regulator of Insulin Gene Transcription J. Biol. Chem., March 25, 2005; 280(12): 11887 - 11894. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Schonhoff, M. Giel-Moloney, and A. B. Leiter Minireview: Development and Differentiation of Gut Endocrine Cells Endocrinology, June 1, 2004; 145(6): 2639 - 2644. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Le Lay, T.-a. Matsuoka, E. Henderson, and R. Stein Identification of a Novel PDX-1 Binding Site in the Human Insulin Gene Enhancer J. Biol. Chem., May 21, 2004; 279(21): 22228 - 22235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-a. Matsuoka, L. Zhao, I. Artner, H. W. Jarrett, D. Friedman, A. Means, and R. Stein Members of the Large Maf Transcription Family Regulate Insulin Gene Transcription in Islet {beta} Cells Mol. Cell. Biol., September 1, 2003; 23(17): 6049 - 6062. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. van Heyningen and K. A. Williamson PAX6 in sensory development Hum. Mol. Genet., May 15, 2002; 11(10): 1161 - 1167. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |