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1、上海交通大学硕士学位论文三种单基因突变糖尿病的基因筛查和临床特点研究姓名：万慧申请学位级别：硕士专业：内科学指导教师：贾伟平20070401上海交通大学硕士学位论文 结果： 1）先证者及其母亲胰岛素受体基因 2 号外显子编码 83 位氨基酸的密码子杂合突变即 Arg Gln (CGG-CAG)，该突变位于胰岛素受体亚基胰岛素结合区，父亲未携带此突变，此突变为国际上首次发现的新突变； 2）先证者胰岛素受体基因 17 号外显子编码 1028 位氨基酸的密码子杂合突变即Ala Val (GCG-GTG)，该突变位于胰岛素受体亚基酪氨酸激酶结构域，双亲均未携带该突变，为先证者自发突变； 3）本次研究共
2、发现胰岛素受体基因的 12 个多态位点，其中内含子 11 的一个多态位点为新发位点，外显子 8，9，13，17 五个多态为同义突变，其余多态位点均位于非编码区。 结论： 本课题发现了中国人第一例 Rabson-Mendenhall 综合征患者， 并在基因水平予以证实。其胰岛素受体基因 2 号外显子 R83Q 杂合突变以及 17 号外显子 A1028V 杂合突变可能是导致该先证者高胰岛素血症及严重胰岛素抵抗的主要原因。 关键词： Rabson-Mendenhall 综合征；胰岛素受体；基因突变 上海交通大学硕士学位论文 第二部分：第二部分： 单基因突变糖尿病与单基因突变糖尿病与 2 型糖尿病临床
3、特点的研究型糖尿病临床特点的研究 目的： 青少年发病的成年型糖尿病、线粒体基因突变引起的糖尿病以及胰岛素受体基因突变引起的糖尿病是目前已经证实的单基因突变糖尿病。前两者容易与 2 型糖尿病相混淆，本研究选择上海市第六人民医院内分泌代谢科，上海市糖尿病研究所以往筛查到的MODY3/5以及线粒体基因突变糖尿病与早发2型糖尿病的临床特点进行比较，探讨单基因突变糖尿病与 2 型糖尿病之间临床特点的差异。 研究对象和方法： 1）选择 22 例（女 15 例/男 7 例）携带线粒体 tRNALeu(UUR)A3243G 基因突变的糖尿病患者以及 13 例（女 7 例/男 6 例）携带 HNF1或 HNF1
4、基因突变的 MODY患者，分别与 151 例（女 80 例/男 71 例）2 型糖尿病患者比较起病年龄、体脂参数、空腹血糖、胰岛素、C 肽及稳态模型评估法评估胰岛素抵抗（HOMA-IR）和胰岛细胞功能（HOMA-B） 。 2）比较 11 例非糖尿病的线粒体基因突变携带者与 82 例无此突变的正常糖耐量人群两组间的糖脂代谢指标。 结果： 1）线粒体基因突变糖尿病组体重指数、腰臀比、胰岛素作用和分泌的简易指标（HOMA-IR、HOMA-B）及空腹胰岛素水平均明显低于 2 型糖尿病组（T2DM） ，高密度脂蛋白-胆固醇（HDL-C）显著高于 T2DM 组；MODY 组低密度脂蛋白-胆固醇（LDL-C
5、）和空腹 C 肽低于 T2DM 组，而 HDL-C 比 T2DM 组高。 2）糖耐量正常的线粒体基因突变携带者与非携带者之间的糖脂代谢参数无统计学差异。 上海交通大学硕士学位论文 结论： 与 2 型糖尿病相比，单基因突变糖尿病（线粒体基因突变糖尿病、MODY）发病较早，体形偏瘦，胰岛细胞分泌功能明显降低。 关键词： 单基因突变；线粒体；MODY；2 型糖尿病 上海交通大学硕士学位论文 Abstracts Part 1: Investigation of insulin receptor gene mutations of a Chinese patient with Rabson-Menden
6、hall syndrome Objective: Mutations in insulin receptor gene will cause a series of severe insulin resistance symptoms which are known as genetic insulin resistance syndromes, including type A insulin resistance syndrome, Rabson-Mendenhall syndrome and leprechaunism. In this study we screened for the
7、 insulin receptor gene mutation in a proband who was diagnosed as Rabson-Mendenhall syndrome as well as her first degree relatives to investigate the mechanism of insulin resistance in receptor level and pathophysiology of Rabson-Mendenhall syndrome. Subjects and Methods: The proband is a girl of 11
8、 years old who was diagnosed as Rabson-Mendenhall syndrome. Her blood glucose and HbA1c had already reached 22.9 mmol/L and 12.5% separately. Shes insensitive to insulin and oral antidiabetic drug. General examination exhibited that her stature is 1.25 m, weight is 23 kg, BMI is 14.72 kg/m2. We also
9、 found her premature during communication as well as acanthosis nigricans, low hairline, typical coarse facial features, hirsutism, advanced dentition, thickened nails and enlarged clitoris by physical examination. Hyperinsulinemia and severe insulin resistance were showed according to the laborator
10、y results. Her family history was negative for diabetes mellitus and related metabolism disorders. Her parents were not consanguineous and exhibited normal phenotype. clinical information on her parents are temporarily unavailable. Genomic DNA of the patient and her parents were extracted from perip
11、heral blood samples using standard phenol /chloroform method. Mutation scanning of insulin receptor 上海交通大学硕士学位论文 gene (22 exons and flanking introns) of the proband was performed using PCR and direct screening of each purified products. We then determined the variations and corresponding amino acid
12、changes in accordance to the standard sequence published in Pubmed. Results: 1) Heterozygous missense mutation of R83Q (CGG-CAG) in exon 2 located in the insulin binding domain of subunit was identified in both the proband and her mother. The locus has not been reported previously. 2) A spontaneous
13、heterozygous mutation of A1028V in exon 17 (GCG-GTG) located in tyrosine kinase domain of subunit was found only in proband. 3) We also found 12 polymorphisms of the insulin receptor gene in this study. They are not only from the patient but also from her parents and normol controls. Among all of th
14、ese singal nucleotide polymorphism sites, eleven of them can be checked in the SNP database except the one in intron 11. Five samesense mutations in exon 8,9,13,17 were observed and others are in the noncoding regions. Conclusion: This is the first patient with Rabson-Mendenhall syndrome caused by t
15、he mutation in insulin receptor gene in China. The heterozygous mutation of R83Q in exon 2 and A1028V in exon 17 may play a major role in hyperinsulinemia and severe insulin resistance of this patient. Key words: Rabson-Mendenhall syndrome；Insulin receptor；Gene mutation 上海交通大学硕士学位论文 Part 2: Study of
16、 clinical features between monogenic diabetes and type 2 diabetes Objective: Maturity Onset Diabetes of the Young, Mitochondrial gene mutation Diabetes Mellitus and insulin receptor gene mutation diabetes mellitus were three kinds of monogenic diabetes which have already been confirmed. The patients with the former two kinds of diabetes are usually mixed in patients with normal type 2 diabetes. In this study, patients with MODY3, MODY5, mitochondrial tRNALeu(UUR)A3243G gene mut
