Mutations of ATP7B gene in wilson disease in Japan: Identification of nine mutations and lack of clear founder effect in a Japanese population
Mutations of ATP7B gene in wilson disease in Japan: Identification of nine mutations and lack of clear founder effect in a Japanese population
复制标题
日本威尔逊病中 ATP7B 基因的突变：在日本人群中鉴定出九种突变且缺乏明确的奠基者效应
DOI：
10.1002/humu.13801101100
复制
发表时间：
1998
期刊：
影响因子：
3.9
通讯作者：
K. Kikuchi
中科院分区：
文献类型：
--
作者：
A. Yamaguchi;A. Matsuura;S. Arashima;Y. Kikuchi;K. Kikuchi
威尔索病（WND）是一种以常染色体隐性方式遗传的先天性铜代谢异常。我们在这里报告了一项关于日本人 WND 相关突变和单倍型的研究。威尔逊病 (WND) 是一种先天性铜代谢缺陷，其肝脏和神经系统症状归因于铜积累，主要在肝脏中，随后由于肝铜池溢出而在大脑和其他组织中积累（Bull 和 Cox，1994）。 WND 基因 ATP7B 编码 P 型 ATP 酶（Bull 等，1993；Petrukhin 等，1993；Tanziet 等，1993）。对 ATP7B 基因的分析揭示了 WND 患者中总共 41 个致病突变（Figus 等，1995；Thomas 等，1995a、b、c）。这些突变与北欧、地中海、南亚、中东和中国血统的人的单倍型之间存在一些关系（Bowcock 等，1994；Petrukhin 等，1994；Thomas 等，1994）。 Shimizu 等人 (1995) 发现内含子 4 中的突变导致日本 WND 患者的 RNA 剪接异常。对从 11 个 WND 家庭中 12 名受影响者（包括第 5 个家庭中的兄弟姐妹病例）和 24 名未受影响成员（无已知血缘关系）获得的 DNA 样本，分析了与 WND 基因座紧密连锁的三个短串联重复 (STR) 标记 D13S314、D13S301 和 D13S316。图 1 显示了 1 个韩国 WND 家族和 7 个日本 WND 家族的单倍型和谱系结果。四种单倍型； 11-2-7、ll-3-7,751-4 和 8.5-6-5.5 (7) 按 D13s3 14-D 13S30 1-D 13S3 16 的顺序在不同家族起源的 WND 染色体中发现，频率分别为 4/16、4/16、2/16 和 2/16，尽管 1/16正常染色体具有 11-2-7 单倍型。韩国家族（家族7）没有这些单倍型，但日本WND染色体的85.7%（12/14）可以由这四种常见的单倍型解释。 ATP7B基因的所有2×1外显子，包括周围的外显子边界，均按照先前所述进行扩增和测序（Petrukhin等人，1994；Thomas等人，1995a）。我们当前的分析中发现了 ATP7B 编码区的九个突变。在韩国人和日本人的 3 条 WND 染色体上发现了两种突变，即中国人报道的 R779L 突变以及意大利人和土耳其人报道的 N1271S 突变（Figus 等，1995；Thomas 等，1995c）（图 1）。日本WND染色体中发现7个新突变；四个错义突变 A875V R92OG、G1187S 和 D1268A，以及三个移码突变 4100delTG、2662delG 和 2874delC。 G1187S 突变是通过检测三名日本 WND 患者外显子 16 中第 3559 位的 G 到 A 的转变来确定的。该突变位于内含子 16 中已知突变 3559+ 1 G 至 A 上游 1 bp。这 6 个错合突变很可能是致病突变，因为检查了相应的外显子（R779L 为外显子 8、A875V 为外显子 11、R92OG 为外显子 12、G1187S 为外显子 16、G1187S 为外显子 16、外显子 18 为致病突变）。 D1268A和N1271S)在54条正常日本染色体组中未发现这种突变。我们还发现了一些可能对 ATP7B 蛋白没有影响的核苷酸改变；
Wilso $ disease (WND) is an inborn error of copper metabolism inherited in an autosomal recessive manner. We here report a study of mutations and haplotypes associated with WND in the Japanese. Hepatic and neurological symptoms of Wilson disease (WND), an inborn error of copper metabolism, are ascribed to copper accumulation, primarily in the liver, and subsequently in the brain and other tissues as a result of overflow of the hepatic copper pool (Bull and Cox, 1994). The WND gene, ATP7B, encodes a P-type ATPase (Bull et al., 1993; Petrukhin et al., 1993; Tanziet al., 1993). Analysis of theATP7B gene revealed a total of 41 disease-causing mutations in WND patients (Figus et al., 1995; Thomas et al., 1995a, b, c). There were some relations between these mutations and haplotypes in persons of northern European, Mediterranean, South Asian, Middleeastern, and Chinese descent (Bowcock et al., 1994; Petrukhin et al., 1994; Thomas et al., 1994). Shimizu et al.(1995) found a mutation in intron 4 that causes aberrant RNA splicing in Japanese WND patients. Three short tandem repeat (STR) markers, D13S314, D13S301, and D13S316, closely linked to the WND locus were analysed on DNA samples obtained from 12 affected (including a sibling case in family 5) and 24 unaffected members of 11 WND families without known consanguinity. Results of haplotyping and pedigrees for one Korean and seven Japanese WND families are shown in Figure 1. Four haplotypes; 11-2-7, ll-3-7,751-4, and 8.5-6-5.5 (7) in the order D13s3 14-D 13S30 1-D 13S3 16 were found in WND chromosomes of different familial origins with a frequency of 4/16, 4/16, 2/16 and 2/16, respectively, although 1/16 of normal chromosomes had the 11-2-7 haplotype. The Korean family (family 7) did not have these haplotypes, but 85.7%(12/14) of Japanese WND chromosomes could be accounted for by the four common haplotypes. All 2 1 exons of theATP7B gene, including surrounding exodintron boundaries, were amplified and sequenced as previously described (Petrukhin et al., 1994; Thomas et al., 1995a). Nine mutations in the coding region of ATP7B were identified in our current analysis. Two mutations, the R779L mutation reported in Chinese and N1271S in Italians and Turks (Figus et al., 1995; Thomas et al., 1995c) were found in one Korean and three Japanese WND chromosomes (Fig. 1). Seven novel mutations were found in Japanese WND chromosomes; four missense mutations, A875V R92OG, G1187S, and D1268A, and three frameshift mutations, 4100delTG, 2662delG, and 2874delC. G1187S mutation was determined by detection of G to A transition at position 3559 in exon 16 in three Japanese WND patients. This mutation was 1 bp upstream from the known mutation 3559+ 1 G to A in intron 16. These six missence mutations were likely to be disease-causing mutations, because examination of the corresponding exons (exon 8 for R779L, exon 11 for A875V exon 12 for R92OG, exon 16 for G1187S, andexon 18for D1268AandN1271S) inapanelof54 normal Japanese chromosomes revealed no such mutation. We also found several nucleotide alterations that were likely to have no effect on the ATP7B protein;
影响因子：
3.5
作者：
PETRUKHIN, K;LUTSENKO, S;GILLIAM, TC
通讯作者：
GILLIAM, TC
通过多态性微卫星连锁不平衡来完善威尔逊病的位置。
影响因子：
9.8
作者：
Bowcock,AM;Tomfohrde,J;Weissenbach,J;Bonne-Tamir,B;StGeorge-Hyslop,P;Giagheddu,M;Cavalli-Sforza,LL;Farrer,LA
通讯作者：
Farrer,LA