A Missense Mutation of Pax4 Gene (R121W) Is Associated With Type 2 Diabetes in Japanese
- Yoshinori Shimajiri1,
- Tokio Sanke1,
- Hiroto Furuta1,
- Tadashi Hanabusa1,
- Takayuki Nakagawa1,
- Yoshio Fujitani2,
- Yoshitaka Kajimoto2,
- Nobuyuki Takasu3 and
- Kishio Nanjo1
- 1First Department of Medicine, Wakayama University of Medical Science, Wakayama, Japan
- 2Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan
- 3Second Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan
Abstract
Pax4 is one of the transcription factors that play an important role in the differentiation of islet β-cells. We scanned the Pax4 gene in 200 unrelated Japanese type 2 diabetic patients and found a missense mutation (R121W) in 6 heterozygous patients and 1 homozygous patient (mutant allele frequency 2.0%). The mutation was not found in 161 nondiabetic subjects. The R121W mutation was located in the paired domain and was thought to affect its transcription activity through lack of DNA binding. Six of seven patients had family history of diabetes or impaired glucose tolerance, and four of seven had transient insulin therapy at the onset. One of them, a homozygous carrier, had relatively early onset diabetes and slowly fell into an insulin-dependent state without an autoimmune-mediated process. This is the first report of a Pax4 gene mutation that exhibits loss of function and seems to be associated with type 2 diabetes. This work provides significant implications for the Pax4 gene as one of the predisposing genes for type 2 diabetes in the Japanese.
Footnotes
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Address correspondence and reprint requests to Tokio Sanke, Department of Clinical Laboratory Medicine, Wakayama University of Medical Science, 811-1 Kimi-idera, Wakayama 641-8509, Japan. E-mail: sanke-t{at}wakayama-med.ac.jp.
Received for publication 7 June 2001 and accepted in revised form 7 September 2001.
EMSA, electrophoretic mobility shift assay; ICA, islet cell antibody; ivTT, in vitro translation and transcription; OGTT, oral glucose tolerance test; PCR, polymerase chain reaction; SSCP, single-strand conformational polymorphism; TK, thymidine kinase.
