Identification and functional analysis of sulfonylurea receptor 1 variants in Japanese patients with NIDDM
Identification and functional analysis of sulfonylurea receptor 1 variants in Japanese patients with NIDDM
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DOI：
10.2337/diabetes.47.3.476
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发表时间：
1998-03-01
期刊：
影响因子：
7.7
通讯作者：
Oka, Y
中科院分区：
文献类型：
--
作者：
Ohta, Y;Tanizawa, Y;Oka, Y
磺酰脲受体1（SUR 1）是β细胞ATP敏感性K+通道（K-ATP）的重要调节亚基。SUR 1基因突变在NIDDM发病中的可能作用仍有争议，因为有正相关和负连锁结果的报道。因此，用单链构象多态性分析在单核苷酸水平上重新检查了100例日本NIDDM患者的SUR 1基因，我们通过检查该基因的所有39个外显子，总共鉴定了5个氨基酸取代和17个沉默突变，两个罕见的新突变，在1例患者中，在第一个核苷酸结合折叠（NBF）（SUR 1的功能重要区域）中鉴定出外显子20中的（DN）-N-811和外显子21中的（RC）-C-835。两个都是杂合子为了分析可能的功能改变，我们通过在HEK 293 T和COS-7细胞中共表达β细胞内向整流器（BIR）（Kir 6.2），K-ATP的通道亚基，突变的SUR 1来重建突变的K-ATP。在67例对照组中未发现R（275）Q替换，3例对照组中发现（VM）-M-560替换。在先证者家系中，这两种替换均未与NIDDM共分离，先前报道的位于第二NBF的S（1370）A置换在日本受试者中也很常见（等位基因频率0.37），并且在非糖尿病对照受试者中以相等的频率被发现，总之，损伤K-ATP功能的SUR 1突变似乎不是日本人NIDDM易感性的主要决定因素。
The sulfonylurea receptor 1 (SUR1) is an essential regulatory subunit of the beta-cell ATP-sensitive K+ channel (K-ATP). The possible role of SUR1 gene mutation(s) in the development of NIDDM remains controversial as both a positive association and negative linkage results have been reported, Therefore, Re examined the SUR1 gene at the single nucleotide level with single strand conformation polymorphism analysis in 100 Japanese NIDDM patients, We identified a total of five amino acid substitutions and 17 silent mutations by examining all 39 exons of this gene, Two rare novel mutations, (DN)-N-811 in exon 20 and (RC)-C-835 in exon 21, were identified in the first nucleotide-binding fold (NBF), a functionally important region of SUR1, in one patient. each, both heterozygotes. To analyze possible functional alterations, we reconstituted the mutant K-ATP by coexpressing beta-cell inward rectifier (BIR) (Kir 6.2), a channel subunit of K-ATP, mutant SUR1 in HEK293T and COS-7 cells, As demonstrated by the patch clamp technique and rubidium (Rb+) efflux studies, neither mutation alters the properties of channel activities. Two other rare missense mutations, R(275)Q in exon 6 and (VM)-M-560 in exon 12, were also identified, The R(275)Q substitution was not found in 67 control subjects, and (VM)-M-560 was present in three control subjects, Neither of these substitutions appeared to cosegregate with NIDDM in the probands' families, A previously reported S(1370)A substitution located in the second NBF was also common in the Japanese subjects (allelic frequency 0.37), and was found at an equal frequency in nondiabetic control subjects, In conclusion, SUR1 mutations impairing K-ATP function do not appear to be major determinants of NIDDM susceptibility in Japanese.