Novel mutations of cholesteryl ester transfer protein(CETP) gene in Japanese hyperalphalipoproteinemic subjects
Novel mutations of cholesteryl ester transfer protein(CETP) gene in Japanese hyperalphalipoproteinemic subjects
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日本高α脂蛋白血症受试者胆固醇酯转移蛋白（CETP）基因的新突变
DOI：
10.1016/j.cca.2011.11.010
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发表时间：
2012
期刊：
影响因子：
5
通讯作者：
Mabuchi H
中科院分区：
文献类型：
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作者：
Ohtani R;Inazu A;Noji Y;Wakasugi T;Miwa K;Tada H;Kawashiri MA;Noguchi T;Nohara A;Kobayashi J;Koizumi J;Yamagishi M;Mabuchi H
背景：日本一半的高脂蛋白血症（HALP）是由CETP基因突变引起的。除了两种常见突变（D442G和内含子14剪接供体位点+1G>A）外，在日本HALP受试者中发现了一些罕见的CETP突变。方法采用限制性内切片段长度多态性（RFLP）和测序方法对受试者基因组DNA进行scetp基因分析。在转染CETP迷你基因构建体或cDNA表达载体的COS-1细胞中，研究了可能导致剪接缺陷或蛋白质分泌缺陷的突变。结果3例受试者均为c.653_654delGGinsAAAC与内含子14剪接供体+1G b> a复合杂合子、c.658G> a杂合子或L261R纯合子CETP基因突变携带者。c.658G>A突变位于第7外显子的最后一个核苷酸，CETP迷你基因分析证实该突变引起剪接异常。L261R CETP不分泌到细胞的条件培养基中。结论CETP缺失导致的HALP有三个新的基因突变。预测日本人存在较多的罕见CETP基因突变，这些多个罕见突变单独或与每种流行突变的组合分别是轻度至中度或显著性HALP的原因。
BACKGROUNDThe half of hyperalphalipoproteinemia (HALP) in Japan is caused by CETP gene mutations. Other than two prevalent mutations (D442G and Intron 14 splicing donor site +1G>A), some rare CETP mutations are found in Japanese HALP subjects.METHODSCETP gene analysis of genomic DNA from subjects was performed by restriction fragment length polymorphism (RFLP) and sequencing analysis. Mutations which were suspected to cause a splicing defect or a protein secretion defect were investigated in COS-1 cells transfected with a CETP minigene construct or a cDNA expression vector.RESULTSEach of three subjects was identified as a carrier of CETP gene mutation of a compound heterozygote of c.653_654delGGinsAAAC and Intron 14 splicing donor site +1G>A, a heterozygote of c.658G>A or a homozygote of L261R. The c.658G>A mutation was located at the last nucleotide of exon 7, and it was confirmed to cause splicing abnormality revealed by the CETP minigene analysis. The L261R CETP was not secreted to conditioned media of the cells.CONCLUSIONSThree novel CETP gene mutations are responsible for HALP by CETP deficiency. It is predicted that there are more rare CETP gene mutations in Japanese, and these multiple rare mutations alone or a combination with each of prevalent mutations is responsible for mild-to-moderate or marked HALP, respectively.