台灣眼睛皮膚型白化症患者之基因分析 與基因型-表現型之研究：基因檢測之重要性

Abstract

白化症是一種先天性的黑色素生合成異常造成的疾病，由於黑色素的缺乏影響的是全身性的範圍包括全身細胞(皮膚、頭髮以及眼睛)，而造成眼睛皮膚型的白化症(OCA)，倘若色素缺乏只發生在眼睛部份則會造成眼睛型白化症(OA)。典型的白化症患者終其一生都擁有白皙的皮膚、白色的頭髮以及淡顏色的眼睛虹膜，而且也沒有能曬黑的能力，也因為缺乏黑色素容易造成眼睛部份的特殊病變，其中包括視力衰弱以及眼睛震顫等症狀。臨床上眼睛皮膚型白化症可分為四種類型，四種分型都屬於體染色體隱性遺傳模式，國健局公告的疾病發生率約為 1/15,000- / 1/20,000，至少有四種基因(TYR, OCA2, TYRP1以及MATP基因)被證實會造成白化症。但是由於白化症患者臨床表現型的多樣性造成不同類型的白化症臨床表現多有重覆，因此發展與建立白化症基因分析仍有其必然的重要性，以利於提供後續的遺傳諮詢。 本篇論文中收集了來自於36個家庭中的86個樣本數，其中包含了37位白化症患者，同時利用臨床表現紀錄單收集白化症患者的臨床表現，根據臨床的分型診斷來做基因檢測，利用聚合酶連鎖反應(PCR)、高效能液相層吸法(DHPLC)以及自動化定序儀分析來偵測TYR、P以及MATP基因上的點突變，另外使用Gap PCR 以及 Multiplex PCR來偵測P基因上Exon 7的缺失型突變。 結果顯示有24位白化症患者於TYR基因上發現兩個突變點位，有2位患者於TYR基因上發現一個突變點位。而在P基因方面有7位患者有發現兩個突變點位，而有3位患者只在P基因上發現一個突變點位，此外並沒有在MATP基因上發現任何突變點位。因此，本篇論文中的 37位白化症患者於基因分析中有26 (26/37)位在TYR 基因上發現突變，而10 (10/37)位在P基因上發現突變點位，只有一位患者沒有於TYR、P或MATP基因上發現任何突變點位，將此基因分析的結果與臨床表現型做相關性探討。 由於不同的基因發生突變會造成不同類型的白化症，而白化症目前並無治療的方法，因此利用基因分析的結果不但能幫助家族中患有白化者的家庭成員，給予完善的遺傳諮詢及產前診斷，更能藉此研究來建立台灣族群的白化症基因資料庫，了解台灣人常見的白化症類型以及突變好發點位。

The term albinism is applied to define a group of inherited abnormalities of melanin synthesis. The reduction in melanin synthesis can be generalized and involve all melanocytes (including skin, hair follicles, eye etc.), resulting in oculocutaneous albinism (OCA). Classical OCA featured white hair, white skin, and blue eyes, and absence of the ability to tan in the lifelong. In clinical, at least four types of OCA had been categorized. All four types of OCA are inherited as autosomal recessive disorders, and the prevalence rate is between 1/15,000- 1/20,000. At least four genes are responsible for the different types of OCA (TYR, OCA2, TYRP1 and MATP). Due to the overlapping of the clinical manifestations between the OCA subtypes, molecular diagnosis will be helpful in this issue and further genetic counseling. In this study, 86 individuals including 37 affected individuals diagnosed as OCA clinically and their family members were tested by molecular genetic analysis. Strategy with coupling denaturing high-performance liquid chromatography (DHPLC) and automated sequencing analysis was performed for TYR, P and MATP genes. Both Gap PCR and gene dosage analysis by Multiplex PCR strategies were used to detect the possible rearrangement in P gene. The result revealed 24 patients were identified as a compound heterozygous or homozygous mutation and 2 patients only one mutation was identified in the TYR gene. In the P gene, 7 patients were identified as a compound heterozygous or homozygous mutation and 3 patients only one mutation was identified. No mutation was identified in the MATP gene. However, the total of 37 patients, 26 (26/37) patients had mutation in the TYR gene, 10 (10/37) patients had mutation in the P gene, and only one patient was not identified any pathologic mutation in TYR, P or MATP gene. Due to albinism is an incurable and irreversible disease, the families with increased risk for an affected child may seek for genetic counseling and possible prenatal genetic testing. In this study, we had established a reliable, efficient molecular diagnostic platform and mutation database for patients with OCA in Taiwan. However, further studies are still warrant to elucidate the genotype – phenotype correlation in OCA.