| Summary: | 碩士 === 國立臺灣大學 === 分子醫學研究所 === 94 === 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.
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