臺灣家族早發型糖尿病之MODY基因檢測與遺傳諮詢

Abstract

年輕早發型糖尿病 (Maturity Onset Diabetes of the Young, MODY) 為單一基因遺傳之第二型糖尿病 (非胰島素依賴型)。此疾病以自體顯性遺傳模式傳遞並且於年輕成年時期發病。至目前為止，已知有六種不同的基因突變導致MODY。其中一為糖解酵素葡糖激酶基因 (glucokinase; GCK, 與MODY 2有關)，另五種為轉錄因子基因：hepatocyte nuclear factor (HNF) 4a （MODY 1），HNF1a（MODY 3），insulin promoter factor 1（IPF-1【MODY 4】），HNF1b（MODY 5），以及neurogenic differentation factor 1（NEUROD1【MODY 6】）。在MODY中扮演重要角色的五種轉錄因子全部於胰臟表現，並且參與調控胰島素，及其他葡萄糖代謝或是b細胞發育過程中重要蛋白質的表現。在白種人，MODY大部分是HNF1a及GCK突變所引起，意即現今有80%的MODY家族可以進行診斷性及預測性基因檢測。其他約15-20%的MODY家族無法於已知的基因找到突變點，稱為MODY X。然而，在日本人及華人的早發第二型糖尿病中只有10%可以在HNF1a基因找到突變點，大部分無法於已知的MODY基因找到突變點。在此篇研究論文中我們發現一臨床症狀及遺傳特性符合MODY最低診斷標準的家族早發型糖尿病人：家庭成員有連續兩代共三人，於25歲之前被診斷為糖尿病。以直接基因定序法檢測於b細胞分化及成熟過程扮演重要角色的HNF1a及NEUROD1基因突變點。定序基因的編碼區及附近兩側的序列，只於HNF1a發現數個造成氨基酸改變的單一核苷酸多形性 (single nucleotides polymorphism)：I27L, S487N, S574G。然而，據之前的報導，這些氨基酸的變異並不與MODY疾病的產生相關。猜測應該還有未被發現的MODY基因，有待進一步研究。雖然MODY於台灣的流行率甚低，但個案對於糖尿病的遺傳訊息以及MODY基因檢測所隱含的意義之瞭解是很重要的。本論文針對基因檢測之議題亦稍做討論，試著為如何有效地與家族成員溝通提供一些參考準則。

Maturity-onset diabetes of the young (MODY) is a monogenic form of Type 2 (non-insulin-dependent) diabetes mellitus. It is inherited in autosomal dominant fashion and expressed at early adult life. To date, mutations in six different genes are known to cause MODY. One of these genes encodes the glycolytic enzyme glucokinase (GCK, associated with MODY2) and the other five encode transcription factors: hepatocyte nuclear factor (HNF)4a (MODY1), HNF1a (MODY3), insulin promoter factor 1 (IPF-1 [MODY4]), HNF1b (MODY5), and neurogenic differentation factor 1 (NEUROD1 [MODY6]). All five transcription factors that have been shown to have a role in MODY are expressed in pancreatic b cells and regulate the expression of insulin as well as other proteins involved in glucose metabolism and/or b cells development. In Caucasians, MODY is mostly caused by mutations in the HNF1a and GCK genes. It means diagnostic and predictive genetic testing is now possible in 80% of MODY families. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes (MODY X). However, mutations in the HNF1a gene were only found in 10% of Japanese and Chinese patients with early-onset type 2 diabetes. Most MODY patients cannot be explained by known MODY genes. In this study, we examined the genetic and clinical characteristics of a Taiwanese subject with familial early-onset diabetes which fulfilled the minimum criteria for MODY: two consecutive generations of diabetes with three members diagnosed at≦25 years of age. We screened for mutations in the HNF1a and NEUROD1 that play a key role in b–cell differentiation and maturation by direct sequencing. Mutation screening of the coding regions and the flanking intron sequence of both genes showed single nucleotides polymorphisms in HNF1a, several of which resulted in amino acid substitutions: I27L, S487N, and S574G. However, these amino acid sequence variants were not associated with MODY in previous reports. This suggest that there are still unidentified genes in the MODY family and require further study. Although the prevalence of MODY in Taiwan is low, understanding perceptions of genetic information in diabetes and the implication of genetic testing in MODY is important. In this thesis, we try to establish some guidance for issue of genetic testing to provide insights into how to communicate effectively with family members.