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研究生:鄭淑芬
研究生(外文):SHWU-FEN JENQ
論文名稱:在高三酸甘油酯血症中的脂蛋白解脂脢基因突變
論文名稱(外文):The Mutation of Lipoprotein Lipase Gene in Hypertriglyceridemia
指導教授:劉武哲劉武哲引用關係葉振聲葉振聲引用關係
指導教授(外文):Wu-Tse LiuTjin-Shing Jap
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:醫學生物技術研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:1999
畢業學年度:87
語文別:中文
中文關鍵詞:高三酸甘油酯血症脂蛋白解脂脢基因聚合脢鍊反應-單股去氧核糖核酸構形多型性分析核甘酸直接定序簡易限制脢切割法
外文關鍵詞:HypertriglyceridemiaLipoprotein lipase genePCR-SSCPDirect sequencingRestriction enzyme digestion
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脂蛋白解脂脢是負責將乳糜微粒及極低密度脂蛋白的核心三酸甘油酯水解的一種關鍵酵素,能提供脂肪酸給細胞做為能量或儲存來源。脂肪之分解能啟動脂蛋白轉換之連續梯層(cascade),產生低密度脂蛋白及參與高密度脂蛋白的重塑過程。脂蛋白解脂脢可由大部份肝外組織的實質細胞製造,且以脂肪組織、心肌、骨骼肌為主。脂蛋白解脂脢被製造分泌後,經運送到附近微血管,以同型雙體形式藉由與heparan sulphate proteoglycans(HSPG)作用而附著於微血管壁上,以脂蛋白元C-II為輔因子,進行三酸甘油酯之水解。
高三酸甘油酯血症之原因包括原發性遺傳疾病:如家族性高三酸甘油酯血症、家族性脂蛋白解脂脢缺乏、家族性脂蛋白元C-II缺乏及家族性脂蛋白解脂脢抑制因子等。繼發性原因如糖尿病、動情激素治療或抗高血壓藥物治療、酒精服用或自體免疫疾病等因素。脂蛋白解脂脢基因突變和高乳糜微粒血症、第四型高脂血症或家族性複合高脂血症都有密切關係。截至目前為止在不同種族間已有超過70種基因突變被發現。本研究之主要目標在找出臺灣本土高三酸甘油酯血症患者的基因突變種類及比率。
我們利用聚合脢鏈反應-單股去氧核糖核酸構形多型性分析(PCR-SSCP)及聚合脢鏈反應產物的核甘酸直接定序方法(direct sequencing) ,來定位十八例高三酸甘油酯血症患者的基因突變的位置及型態,並利用簡易限制脢切割法快速鑑定家族成員的基因表現。我們共發現四種基因突變及兩種多型性。從核甘酸直接定序發現有1人在表現子3區域乃是在cDNA第547個核甘酸位置之G被A所取代,其相對應脂蛋白解脂脢基因上氨基酸之改變為第98個氨基酸從丙銨酸變成蘇銨酸之異型合子變異。我們發現在表現子6區域共有3人有變異,其中2人在cDNA第1009個核甘酸位置之C被G所取代,其相對應氨基酸之改變為第252個氨基酸從白銨酸變成纈銨酸之異型合子變異。其中一名患者同時有在cDNA第1047個核甘酸位置之C被A所取代,其相對應氨基酸之改變為第264個氨基酸從半胱銨酸變成終止訊息之異型合子變異。另有1人是在cDNA第1001個核甘酸位置之T被C所取代,其相對應氨基酸之改變為第249個氨基酸從異白銨酸變成蘇銨酸之異型合子變異。在表現子8區域乃是共有3人在cDNA第1338個核甘酸位置之C被A所取代,但其第361個相對應氨基酸並未改變,仍是蘇銨酸之異型合子變異。在表現子9區域共有2人乃是在cDNA第1595個核甘酸位置之C被G所取代,其相對應氨基酸之改變為第447個氨基酸從絲銨酸變成終止訊息之異型合子變異,目前一般視此變異為多型性。這其中有一名女性兼具L252V及C264X之變異,另有一名男性則兼具L252V及T361T之多型性。
我們利用限制脢切割或針對突變點附近更改一個鹽基,設計新的序列引子重新做聚合脢鏈反應產生新切點,可以很快區別突變和正常基因。我們進一步對四名有基因突變患者做家族研究。前述一名典型高乳糜微粒血症及反覆胰臟炎發作之女性,她的複合性異型合子可能來自不同的對偶基因。另一名兼具L252V突變及T361T多型性之男性的家族分析顯示突變基因的表現可能和環境因素與基因間的相互作用有關。另外兩名患者因家族成員意願及散居海外,無法得到完整資料。我們認為突變或終止訊息所造出的脂蛋白解脂脢可能會導致這些患者形成高三酸甘油酯血症。利用PCR-SSCP作篩選,加上核甘酸直接定序及限制脢切割應是探討國人在此類疾病及突變基因盛行率之可行方法。

Lipoprotein lipase (LPL; EC 3.1.1.34) is the rate-limiting enzyme for the hydrolyis and removal of chylomicrons and very-low-density lipoprotein (VLDL) triglycerides from the circulation, providing cells with fatty acid for either energy or storage. Lipolysis also initiates a cascade of conversion of lipoprotein particles, which result in circulating low-density lipoprotein (LDL) and in the remodeling of high-density lipoprotein (HDL). LPL is synthesized by the parenchymal cells of extrahepatic tissues, most notably adipose tissue, heart and muscle, and is secreted and transported to the luminal surface of vascular endothelium where catalysis occurs. LPL functions as a homodimer bound to the heparan sulfate proteoglycans at the surface of capillary endothelium to hydrolyze triglycerides, using apolipoprotein CII (ApoC-II) as a cofactor.
The causes of hypertriglyceridemia can be due to primary inherited disorders such as familial hypertriglyceridemia, familial LPL deficiency, apolipoprotein C-II deficiency, and circulating inhibitor of LPL; or due to acquired causes such as diabetes mellitus, estrogen or antihypertensive drug therapy, alcohol use, and autoimmune disease. Mutations of the LPL gene have been associated with chylomicronemia, type IV、V hyperlipidemia and familial combined hyperlipidemia. Over 70 mutations have been found in different populations. Our aim is to find the type and frequency of LPL gene mutation in local hypertriglyceridemia subjects.
By using PCR-SSCP technique and PCR product direct DNA sequencing, we were able to screen and detect the genetic mutation in the lipoprotein lipase gene among eighteen hypertriglyceridemia patients. We also applied restriction enzyme digestion method for easy, fast screening of the corresponding family members. We found four LPL gene mutations and two polymorphisms. Direct DNA sequencing revealed one patient with a missense mutation in exon 3, a G to A transition for codon 98 at nucleotide 547, resulting in a Ala to Thr heterozygous substitution. We found 3 patients with abnormal band shift in exon 6, for which direct sequencing revealed that one patient among the three had a missense mutation, a C to G transversion for codon 252 at nucleotide 1009, resulting in a Leu to Val heterozygous substitution. The same patient also had a nonsense mutation, a C to A transversion for codon 264 at nucleotide 1047, resulting in a Cys to stop codon heterozygous substitution. The second patient also showed L252V mutation. The third patient was found with a missense mutation, a T to C transition for codon 249 at nucleotide 1001, resulting in a Ile to Thr heterozygous substitution. Three other patients were found with abnormal band shift in exon 8, for which direct sequencing revealed a silent mutation, a C to A transversion for codon 361 at nucleotide 1338; the amino acid remained the same as Thr. We found 2 patients with abnormal band shift in exon 9, for which direct sequencing revealed a missense mutation, a C to G transversion for codon 447 at nucleotide 1595, resulting in a premature Ser to stop codon heterozygous substitution, which is often referred as a polymorphism. There was one subject with compound heterozygous L252V & C264X mutation, and another subject with L252V mutation & T361T polymorphism.
By applying restriction enzyme digestion or by redesigning a new primer which replaced a base near the mutation site to create a new cutting site, we were able to differentiate the mutation codon from the normal codon easily. We did further family pedigree studies for the four patients with mutations. One female patient with typical chylomicronemia and recurrent pancreatitis had the compound heterozygous mutation with each one in a different allele. The pedigree study of a male with L252V mutation & T361T polymorphism indicated that the expression of mutation might have been affected by the environment and gene interactions. We were unable to reach any conclusions for the other two patients due to the unwillingness of their family members. In conclusion, these mutated or truncated lipoprotein lipase may lead to hypertriglyceridemia in the studied patients. For the prevalence and for early diagnosis of lipoprotein lipase defect, PCR-SSCP followed by direct sequencing and restriction enzyme digestion seems to be a feasible approach.

第一章 緒論
第二章 材料與方法
第三章 結果
第四章 討論
第五章 參考文獻
第六章 圖表

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