台灣人多囊性肝病之基因研究

Genetic Predisposition of Taiwanese Patients with Polycystic Liver Disease

楊安民(An-Ming Yang)

指導教授 ： 楊偉勛

國立臺灣大學/醫學院/分子醫學研究所/碩士(2006年)

https://doi.org/10.6342/NTU.2006.01405

摘要

在肝膽胃腸科醫師的日常工作當中，多囊性肝病的病人並不在少數，其疾病的嚴重度相差甚大，雖然大部分的肝囊腫病人都無症狀，但在某些具有較大型或較多肝囊腫的病人卻也常造成腹痛、腹脹或影響呼吸等症狀；臨床觀察上，多囊肝也有家族群聚的現象。
單純的多囊性肝病在近年來的研究當中已被認為是獨立於多囊性腎病的疾病，在白種人的研究中，體染色體PRKCSH基因突變及SEC63基因突變可在約三分之一的病人身上找到，而這兩個基因都與細胞內質網中Glucosidase II β的功能喪失有關，Glucosidase II β的功能喪失使得蛋白質Hepatocystin的功能喪失而導致病人在成年後漸漸產生多發性肝囊腫並進而引起各種病理變化、影響病人健康。
在我們的研究之中，我們首先用一年的時間觀察統計在健檢中心接受腹部超音波檢查發現有肝囊腫者的年齡別發生率，我們發現就所有肝囊腫患者而言，其年齡別發生率從30歲以下的0.17％隨者年齡逐漸升高，到55至60歲之間達到14.29％，然後不再增加；就多囊肝而言，40歲以下並無患者，40歲至45歲間盛行率為0.15％，到50歲至55歲之間達到1.5％，然後盛行率也不再增加，這種到一定年齡盛行率便不再增加的情形代表的意義仍待研究。
我們接下來收集了20個多囊肝的指標個案，其中10個指標個案有明確的家族群聚的現象，我們針對在白種人報告過的PRKCSH基因對指標個案進行全基因的基因定序，發現只有在Exon 11有一廣泛存在的GAG deletion，這項基因多型性導致所形成的蛋白質缺少一個Glutamic acid，其餘在白種人發表過的基因突變在台灣人身上都找不到，這個結果可證明PRKCSH的突變在白種人是一種Founder effect，可能與東方人無關，然而exon 11的基因多型性是否與多囊肝有關？
我們進行了針對一般族群的DNA fragment analysis，發現在一般族群中exon 11的多型性其對偶基因頻率與多囊肝患者非常接近，所以這個多型性應與多囊肝無關，但是是否與一般的肝囊腫發生有關則需要再進一步的研究。

關鍵字

多囊性肝病 ； 基因

並列摘要

As a gastroenterologist, patients with liver cysts are frequently encountered in our daily practice. Although most patients with liver cysts are asymptomatic, some patients with multiple massive hepatic cysts may experience abdominal pain, discomfort and shortness of breath correlating with severity of hepatic cystic disease. Also, family clustering was found in patients with polycystic liver disease.
In the previous study, isolated polycystic liver disease has been proved to be independent of autosomal dominant polycystic kidney disease. Recently, germline mutations in PRKCSH and SEC63 genes were found to be responsible for development of PCLD. The PRKCSH gene encode a known protein -Glucosidase II β- which was a subunit of the enzyme Glucosidase acts in the endoplasmic reticulum for maintaining the intact of epithelium. Once the function impaired, liver cysts developed gradually with aging process and caused many pathological conditions.
In our study, we collected patients with liver cysts who received abdominal ultrasonography in a health evaluation center in one year. As far as liver cysts are concerned, the prevalence of liver cysts increased with age. For patients under 30-year-old, the prevalence was 0.17% with the advancing of age, the prevalence reached 14.29% in age 55 to 60 but did not elevated any more. For patients with polycystic liver disease, there is none under 40-year-old, the prevalence in 40 to 45 was 0.15% and increased to 1.5% in 50 to 55 years old. Then, the prevalence keep in that level. Why the prevalence did not increase after the age merits further study.
Then, we collect 20 index cases with polycystic liver disease，10 of these cases with significant family history. We did full length direct gene sequencing for PRKCSH in these patients. The only finding is there is a GAG deletion in exon 11 among 9 of the 20 patients. All mutations reported in the western literature was not found in Taiwanese. This result indicated that then mutations in this gene may be founder effect of Caucasian. However, does the GAG deletion which caused a loss of Glutamic acid associated with polycystic liver? We thus conducted a DNA fragment analysis on this exon among 56 Taiwanese general population. We found that the allele frequency is similar to that of polycystic liver disease patients, therefore, this polymorphism has nothing to do with PCLD. However, whether this polymorphism is associated with the development of liver cyst needs further studies.

並列關鍵字

Polycystic Liver Disease ； Genetic Predisposition

參考文獻

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