An In-Frame Deletion in Kir6.2 (KCNJ11) Causing Neonatal Diabetes Reveals a Site of Interaction between Kir6.2 and SUR1

被引:18
作者
Craig, Tim J. [1 ]
Shimomura, Kenju [1 ]
Holl, Reinhard W. [3 ]
Flanagan, Sarah E. [2 ]
Ellard, Sian [2 ]
Ashcroft, Frances M. [1 ]
机构
[1] Univ Oxford, Dept Physiol Anat & Genet, Henry Wellcome Ctr Gene Funct, Oxford OX1 3PT, England
[2] Peninsula Med Sch, Inst Biomed & Clin Res, Exeter EX2 5DW, Devon, England
[3] Univ Ulm, Inst Epidemiol, D-89081 Ulm, Germany
基金
英国惠康基金;
关键词
K-ATP CHANNELS; SULFONYLUREA RECEPTOR; INSULIN-SECRETION; ACTIVATING MUTATIONS; DEND-SYNDROME; N-TERMINUS; STOICHIOMETRY; TRAFFICKING; INHIBITION; MECHANISM;
D O I
10.1210/jc.2009-0159
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Context: Activating mutations in genes encoding the Kir6.2 (KCNJ11) and SUR1 (ABCC8) subunits of the pancreatic ATP-sensitive K+ channel are a common cause of permanent neonatal diabetes (PNDM). All Kir6.2 mutations identified to date are missense mutations. We describe here a novel in-frame deletion (residues 28-32) in Kir6.2 in a heterozygous patient with PNDM without neurological problems that are detectable by standard evaluation. Objective: The aim of the study was to identify the mutation responsible for neonatal diabetes in this patient and characterize its functional effects. Design: Wild-type and mutant Kir6.2/SUR1 channels were examined by heterologous expression in Xenopus oocytes. Results: The Kir6.2-28 Delta 32 mutation produced a significant decrease in ATP inhibition and an increase in whole-cell K-ATP currents, explaining the diabetes of the patient. Tolbutamide block was only slightly reduced in the simulated heterozygous state, suggesting that the patient should respond to sulfonylurea therapy. The mutation decreased ATP inhibition indirectly, by increasing the intrinsic (unliganded) channel open probability. Neither effect was observed when Kir6.2 was expressed in the absence of SUR1, suggesting that the mutation impairs coupling between SUR1 and Kir6.2. Coimmunoprecipitation studies further revealed that the mutation disrupted a physical interaction between Kir6.2 and residues 1-288 (but not residues 1-196) of SUR1. Conclusions: We report a novel KCNJ11 mutation causing PNDM. Our results show that residues 28-32 in the N terminus of Kir6.2 interact both physically and functionally with SUR1 and suggest that residues 196-288 of SUR1 are important in this interaction. (J Clin Endocrinol Metab 94: 2551-2557, 2009)
引用
收藏
页码:2551 / 2557
页数:7
相关论文
共 34 条
[1]   KATP channels and insulin secretion:: a key role in health and disease [J].
Ashcroft, FM .
BIOCHEMICAL SOCIETY TRANSACTIONS, 2006, 34 :243-246
[2]   ATP-sensitive potassium channelopathies: focus on insulin secretion [J].
Ashcroft, FM .
JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (08) :2047-2058
[3]   ATP-sensitive K+ channels and disease:: from molecule to malady [J].
Ashcroft, Frances M. .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2007, 293 (04) :E880-E889
[4]   SUR domains that associate with and gate KATP pores define a novel gatekeeper [J].
Babenko, AP ;
Bryan, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (43) :41577-41580
[5]   Two regions of sulfonylurea receptor specify the spontaneous bursting and ATP inhibition of KATP channel isoforms [J].
Babenko, AP ;
Gonzalez, G ;
Bryan, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (17) :11587-11592
[6]   SUR-dependent modulation of KATP channels by an N-terminal KIR6.2 peptide -: Defining intersubunit gating interactions [J].
Babenko, AP ;
Bryan, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (46) :43997-44004
[7]   The N-terminus of KIR6.2 limits spontaneous bursting and modulates the ATP-inhibition of KATP channels [J].
Babenko, AP ;
Gonzalez, G ;
Bryan, J .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1999, 255 (02) :231-238
[8]   N-terminal transmembrane domain of the SUR controls trafficking and gating of Kir6 channel subunits [J].
Chan, KW ;
Zhang, HL ;
Logothetis, DE .
EMBO JOURNAL, 2003, 22 (15) :3833-3843
[9]   Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype [J].
Flanagan, SE ;
Edghill, EL ;
Gloyn, AL ;
Ellard, S ;
Hattersley, AT .
DIABETOLOGIA, 2006, 49 (06) :1190-1197
[10]   Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes [J].
Girard, Christophe A. J. ;
Shimomura, Kenju ;
Proks, Peter ;
Absalom, Nathan ;
Castano, Luis ;
de Nanclares, Guiomar Perez ;
Ashcroft, Frances M. .
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 2006, 453 (03) :323-332