Clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent neonatal diabetes mellitus. Issue 3 (11th March 2013)

• Record Type: Journal Article
• Authors: Takagi, Tomoyuki; Furuta, Hiroto; Miyawaki, Masakazu; Nagashima, Kazuaki; Shimada, Takeshi; Doi, Asako; Matsuno, Shohei; Tanaka, Daisuke; Nishi, Masahiro; Sasaki, Hideyuki; Inagaki, Nobuya; Yoshikawa, Norishige; Nanjo, Kishio; Akamizu, Takashi
• Is Part Of: Journal of diabetes investigation. Volume 4:Issue 3(2013:Jun.)
• Page Start: 269
• Page End: 273
• Publication Date: 2013-03-11
• Subjects: Diabetes -- Periodicals; Diabetes -- Research -- Periodicals; Diabetes Mellitus -- Periodicals; 616.462005
• DOI: 10.1111/jdi.12049
• Languages: English
• ISSNs: 2040-1116

Abstract

<abstract abstract-type="main" id="jdi12049-abs-0001"> <title>Abstract</title> <sec id="jdi12049-sec-0001" sec-type="section"> <title>Aims/Introduction</title> <p>The adenosine triphosphate (ATP)‐sensitive potassium (K<sub>ATP</sub>) channel is a key component of insulin secretion in pancreatic β‐cells. Activating mutations in <italic>ABCC8</italic> encoding for the sulfonylurea receptor subunit of the K<sub>ATP</sub> channel have been associated with the development of neonatal diabetes mellitus (NDM). The aim was to investigate clinical and functional characterization of the Pro1198Leu <italic>ABCC8</italic> gene mutation associated with permanent NDM (PNDM).</p> </sec> <sec id="jdi12049-sec-0002" sec-type="section"> <title>Materials and Methods</title> <p>The coding regions and conserved splice sites of <italic>KCNJ11</italic>, <italic> ABCC8</italic> and <italic>INS</italic> were screened for mutations in a 12‐year‐old girl diagnosed with PNDM. The functional property of the mutant channel identified was examined with patch‐clamp experiments in COS‐1 cells. We also investigated the difference of effectiveness between two groups of oral sulfonylureas <italic>in vitro</italic> and in the patient.</p> </sec> <sec id="jdi12049-sec-0003" sec-type="section"> <title>Results</title> <p>We identified a heterozygous missense mutation (c.3593 C>T, Pro1198Leu) in <italic>ABCC8</italic>. The mutated residue (P1198) is located within a putative binding site of sulfonylureas, such as tolbutamide or gliclazide. In patch‐clamp experiments, the mutant channel was less ATP sensitive than the wild type. Furthermore, the sensitivity to tolbutamide was also reduced in the mutant channel. In addition to the tolbutamide/gliclazide binding site, glibenclamide is thought to also bind to another site. Glibenclamide was more effective than other sulfonylureas <italic>in vitro</italic> and in the patient. The treatment of the patient was finally able to be switched from insulin injection to oral glibenclamide.</p> </sec> <sec id="jdi12049-sec-0004" sec-type="section"> <title>Conclusions</title> <p>We identified the Pro1198Leu <italic>ABCC8</italic> mutation in a PNDM patient, and clarified the functional and clinical characterization. The present findings provide new information for understanding PNDM.</p> </sec> </abstract>