跳到主要內容

臺灣博碩士論文加值系統

(44.200.194.255) 您好!臺灣時間:2024/07/23 03:34
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:陳遊
研究生(外文):Yu Chen
論文名稱:應用外顯子定序來找出年輕人之成熟期發病型糖尿病的基因
論文名稱(外文):Application of whole-exome sequencing to identify genes for Maturity-Onset Diabetes of the Young (MODY)
指導教授:楊偉勛楊偉勛引用關係陳沛隆陳沛隆引用關係
指導教授(外文):Wei-Shiung YangPei-Lung Chen
口試委員:張以承
口試委員(外文):Yi-Cheng Chang
口試日期:2018-06-11
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:分子醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2018
畢業學年度:106
語文別:中文
論文頁數:104
中文關鍵詞:年輕人之成熟期發病型糖尿病全外顯子定序分子學基因診斷胰島素葡萄糖激酶
相關次數:
  • 被引用被引用:0
  • 點閱點閱:241
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
年輕人之成熟期發病型糖尿病屬於家族性體染色體顯性遺傳糖尿病,特徵為單基因失活性變異,所造成的胰島素分泌與作用機制發生缺陷。發病年齡較早,通常小於25歲,且體型外觀較瘦,因此容易與第1型糖尿病混淆。不同於第1型糖尿病患者須終身施打胰島素,特定基因型的年輕人之成熟期發病型糖尿病患者,如:GCK-MODY,青少年時期可藉由運動及飲食控制血糖。其他如:HNF4A-MODY、HNF1A-MODY、ABCC8-MODY、KCNJ11-MODY首選的降血糖藥物建議為磺胺尿素類,而非第2型糖尿病首選用藥二甲雙胍類。基因診斷對此類遺傳性糖尿病,扮演著調整治療方針與評估疾病進展的重要角色。目前已知14個基因(HNF4A、GCK、HNF1A、PDX1、HNF1B、NEUROD1、KLF11、CEL、PAX4、INS、BLK、ABCC8、KCNJ11、APPL1)會導致年輕人之成熟期發病型糖尿病,然而亞洲族群中,超過80%的患者,其基因型並非以上的14個,屬於基因未明型。在考量樣本數較少以及花費成本後,我們應用全外顯子定序的方式,試圖尋找台灣此類型遺傳性糖尿病的致病基因。
本研究經臨床診斷為年輕人之成熟期發病型糖尿病表現型患者,可納入本研究。納入條件為個案25歲前患有糖尿病或糖尿病前期的症狀,不具有第1型和第2型糖尿病典型的臨床表徵,且至少有兩代家族性遺傳的糖尿病史,以及父母其中一方是糖尿病患者,可加入研究與接受遺傳諮詢。在2017年,我們收案了2個符合年輕人之成熟期發病型糖尿病表現的家族,包含5名患者與1名未罹病者,男女比1:1,並以NA12878作為對照組標準品,共計7個樣本。委外使用Agilent SureSelect V6 Exon kit擷取人類基因體中的全外顯子序列後,以Illumina Hiseq進行次世代定序,平均7個樣本生成的序列425926569±6273250.0條,高達99.72%的序列是成對且對齊在參考序列hg19上,在10倍深度下標的區域覆蓋率為93.77%,平均定序深度是51.46倍,其中89.30%鹼基的定序品質(Q值)至少等於30。經由標準化的生物資訊處理流程(BWA-MEM、Picard、GATK、GATK/HaplotypeCaller、ANNOVAR),平均註解的SNVs與Indels數為390775.6±44822.0個,藉由親本三元體與共分離的分析方式,分別選出患者家族內共同的變異點位,其最小等位基因頻率在基因資料庫中(Esp6500、1000 Genomes Project、ExAC)均小於0.01,而在多項軟體預測的條件中,排除多型性表現型預測為良性的變異點位(Polyphen2_HVAR_score ≦0.446)或排除胺基酸置換不影響蛋白質功能的點位(SIFT > 0.05)。利用罕見單基因糖尿病之105個基因清單中,篩選出致病點位,再利用桑格定序做確認。最後,成功地在兩個家族分別找出致病點位(INS, c.125T>C;p.V42A)和(GCK,c.1318G>T;p.E440X)。
我們在台灣族群第一次發現這2個點位,皆位於國外文獻記載的致病基因中,且藉由基因型的確診,使我們將更加邁向精準醫療的時代。應用全外顯子次世代定序的基因診斷流程,同樣具有確診性,並提供機會尋找新的致病基因,對於小樣本類型的研究,帶來更有效率及便利的診斷方式。
Maturity-onset diabetes of the young (MODY) is a monogenic diabetes mellitus characterized by an autosomal dominant mode of inheritance. The genetic defects result in insulin secretion or functional impairment. Because of their younger onset age usually less than 25 and their lean physical appearance, MODY patients are easily misdiagnosed as type 1 diabetes (T1D). Compared to T1D patients who need the insulin supplement for whole life, some patients of MODY can be managed with oral hypoglycemic agents or diet. For instance, the first line recommended drug in HNF4A-MODY, HNF1A-MODY, ABCC8-MODY, KCNJ11-MODY is sulfonylurea, not metformin, which is the first line recommended drug for most type 2 diabetes (T2D). Therefore, a correct genetic diagnosis is important to guide the treatment strategies, also to predict disease progress. Although there are at least 14 MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, APPL1) more than 80% of Asian MODY cases cannot be assigned to a specific genetic diagnosis in previous reports. Our aim is to find disease causative genes of MODY families in Taiwan. Considering the cost-effect in a small-sample-size study, we used whole-exome sequencing (WES) for genotyping.
In this study, the inclusion criteria were probands who had atypical manifestations of T1D and T2D, whose age at onset of diabetes or pre-diabetes was less than 25, who had at least 2 generations of familial diabetes history, and one of their parents had diabetes. In 2017, six subjects from two Taiwanese MODY families were enrolled in this study. Genomic DNA of six subjects and one international reference DNA sample (NA12878) were captured by Agilent SureSelect V6 Exon kit and sequenced by Illumina Hiseq. The total generated reads were 425926569±6273250, and 99.72% of reads were properly paired and mapped to the reference sequence (GRCh37/hg19). Eighty-nine point thirty percent of readed bases were at least large than 30 in Phred quality scores (Q scores). The average of targeted coverage of seven samples was 93.77% at 10 folds read depth. The average read depth of seven samples was 51.46 folds. Variants calling were performed by bioinformatic pipelines (BWA-MEM, Picard, GATK, GATK/HaplotypeCaller, ANNOVAR). The average variants of 7 samples were 390775.6±44822.0. After a trio and a co-segregation analysis, disease-causing variants were selected sequentially by minor allele frequency (MAF) less than 0.01 in population databases (Esp6500, 1000 Genomes Project, ExAC), by in silicon functional predictions (by excluded Polyphen2_HVAR_score ≦0.446 as benign or by excluded SIFT > 0.05 as amino acid substitution tolerated), and by a list of 105 DM-related genes (MODY, NDM and other rare form of monogenic diabetes). The final results were confirmed by Sanger sequencing.
Two variants (INS, c.125T>C;p.V42A of insulin) and (GCK, c.1318G>T;p.E440X of glucokinase) were successfully identified respectively in 2 MODY families. In Taiwanese, these two variants were found in the MODY disease-causing genes for the first time. We are going further toward the era of precision medicine by diagnosing diseases with the correct genotyping. This study shows us that WES is a practical and effective method for diagnosing unexplained monogenic disease in small-sample-size studies.
口試委員會審定書......i
誌謝......ii
中文摘要......iii
Abstract......v
目錄......vii
圖目錄......xi
表目錄......xiii
第一章 緒論......1
1.1 糖尿病介紹......1
1.2 糖尿病分類......2
1.2.1 第1型糖尿病......2
1.2.2 第2型糖尿病......2
1.2.3 妊娠糖尿病......3
1.2.4 其他類型糖尿病......3
1.3 年輕人之成熟期發病型糖尿病(Maturity-Onset Diabetes of the Young, MODY)......3
1.3.1 盛行率......4
1.3.2 病生理機制......5
1.3.3 葡萄糖刺激胰島素分泌機轉(相關基因為GCK、ABCC8、KCNJ11) ......5
1.3.4 細胞核內轉錄因子(相關基因為HNF4A、HNF1A、HNF1B、NEUROD1、PDX1/IPF1、KLF11、BLK)......6
1.3.5 誘導胰島β細胞分化(相關基因為PDX1、NEUROD1、PAX4)......8
1.3.6 胰島素與胞內胰島素訊息傳遞(相關基因為INS、APPL1)......8
1.3.7 糖尿病和胰臟外分泌功能異常症候群(相關基因為CEL)......8
1.4 年輕人之成熟期發病型糖尿病的歷史演進......9
1.4.1 HNF4A-MODY(MODY1, OMIM#600281)......9
1.4.2 GCK-MODY(MODY2, OMIM#125851)......10
1.4.3 HNF1A-MODY(MODY3, OMIM#600496)......11
1.4.4 PDX1/IPF1-MODY(MODY4, OMIM#606392)......11
1.4.5 HNF1B/TCF2-MODY(MODY5, Renal cysts and diabetes syndrome, OMIM#137920)......12
1.4.6 NEUROD1-MODY(MODY6, OMIM#606394)......12
1.4.7 KLF11-MODY(MODY7, OMIM#610508)......12
1.4.8 CEL-MODY(MODY8, OMIM#609812)......13
1.4.9 PAX4-MODY(MODY9, OMIM#612225)......13
1.4.10 INS-MODY(MODY10, OMIM#613370)......13
1.4.11 BLK-MODY(MODY11, OMIM#613375)......14
1.4.12 ABCC8-MODY(MODY12)......14
1.4.13 KCNJ11-MODY(MODY13, OMIM#616329)......14
1.4.14 APPL1-MODY(MODY14, OMIM#600509)......15
1.5 年輕人之成熟期發病型糖尿病的治療......15
1.6 年輕人之成熟期發病型糖尿病的遺傳諮詢......15
1.7 年輕人之成熟期發病型糖尿病的基因診斷......16
1.8 全外顯子定序介紹 [69]......17
1.8.1 探針廠牌比較......17
1.8.2 全外顯子定序優點......18
1.8.3 全外顯子定序限制......18
1.8.4 全外顯子定序價格......19
1.9 研究動機......19
第二章 研究方法......21
2.1 研究對象......21
2.1.1 納入條件(修改自ISPAD與ADA指引) [3, 44]......21
2.1.2 排除條件(修改自ISPAD與ADA指引) [3, 44]......21
2.2 受試者來源......22
2.2.1 DF114......22
2.2.2 DF115......23
2.3 研究材料......23
2.4 血液gDNA萃取......23
2.5 全外顯子次世代基因定序......25
2.5.1 樣本前處理......25
2.5.2 全外顯子探針擷取......26
2.5.3 次世代定序......26
2.6 資訊處理介紹......27
2.7 105個單基因糖尿病致病基因清單......29
2.8 聚合酶連鎖反應(Polymerase chain reaction, PCR)與桑格定序(Sanger sequencing)......29
2.8.1 引子設計......30
2.8.2 聚合酶連鎖反應步驟......30
2.9 總流程......30
第三章 研究結果......33
3.1 定序結果統計......33
3.2 單點核苷酸變異(Single nucleotide variants, SNVs)暨小片段的插入缺失(Indels)分析統計......33
3.3 DF114之親本三元體分析(Trio analysis)......35
3.3.1 分析步驟......35
3.3.2 分析結果......36
3.3.3 全外顯子次世代定序及桑格定序結果(DF114)......37
3.4 DF115之共分離分析(Co-segregation analysis)......37
3.4.1 分析步驟......37
3.4.2 分析結果......37
3.4.3 全外顯子次世代定序及桑格定序結果(DF115)......38
第四章 討論......39
4.1 全外顯子定序限制......39
4.2 分析流程限制......39
4.3 族群內的變異點位常數......40
4.4 致病點位的基因型表現型相關性......40
4.4.1 INS(c.125T>C;p.V42A)......40
4.4.2 GCK(c.1318G>T;p.E440X)......42
第五章 結論......45
參考文獻......81
附錄......89
1.Ogurtsova, K., et al., IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract, 2017. 128: p. 40-50.
2.國民健康署, 2017國民健康署年報中文版. https://health99.hpa.gov.tw/educZone/edu_detail.aspx?CatId=21980&kw=, 2018.
3.American Diabetes, A., 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2018. Diabetes Care, 2018. 41(Suppl 1): p. S13-S27.
4.DAROC, Clinical Practice Guidelines for Diabetes Care- 2018, Taiwan, Diabetes, Association of the R.O.C. 2018.
5.Barbour, L.A., et al., Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes. Diabetes Care, 2007. 30 Suppl 2: p. S112-9.
6.Kuhl, C., P.J. Hornnes, and O. Andersen, Etiology and pathophysiology of gestational diabetes mellitus. Diabetes, 1985. 34 Suppl 2: p. 66-70.
7.Hod, M., et al., The International Federation of Gynecology and Obstetrics (FIGO) Initiative on gestational diabetes mellitus: A pragmatic guide for diagnosis, management, and care. Int J Gynaecol Obstet, 2015. 131 Suppl 3: p. S173-211.
8.Bonnefond, A., P. Froguel, and M. Vaxillaire, The emerging genetics of type 2 diabetes. Trends Mol Med, 2010. 16(9): p. 407-16.
9.Yamagata, K., et al., Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature, 1996. 384(6608): p. 458-60.
10.Froguel, P., et al., Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature, 1992. 356(6365): p. 162-4.
11.Yamagata, K., et al., Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature, 1996. 384(6608): p. 455-8.
12.Stoffers, D.A., et al., Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet, 1997. 17(2): p. 138-9.
13.Horikawa, Y., et al., Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. Nat Genet, 1997. 17(4): p. 384-5.
14.Malecki, M.T., et al., Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat Genet, 1999. 23(3): p. 323-8.
15.Neve, B., et al., Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function. Proc Natl Acad Sci U S A, 2005. 102(13): p. 4807-12.
16.Raeder, H., et al., Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genet, 2006. 38(1): p. 54-62.
17.Plengvidhya, N., et al., PAX4 mutations in Thais with maturity onset diabetes of the young. J Clin Endocrinol Metab, 2007. 92(7): p. 2821-6.
18.Edghill, E.L., et al., Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes, 2008. 57(4): p. 1034-42.
19.Molven, A., et al., Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes, 2008. 57(4): p. 1131-5.
20.Borowiec, M., et al., Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction. Proc Natl Acad Sci U S A, 2009. 106(34): p. 14460-5.
21.Bowman, P., et al., Heterozygous ABCC8 mutations are a cause of MODY. Diabetologia, 2012. 55(1): p. 123-7.
22.Bonnefond, A., et al., Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PLoS One, 2012. 7(6): p. e37423.
23.Prudente, S., et al., Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus. Am J Hum Genet, 2015. 97(1): p. 177-85.
24.Shields, B.M., et al., Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia, 2010. 53(12): p. 2504-8.
25.Xu, J.Y., et al., Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients. Eur J Hum Genet, 2005. 13(4): p. 422-7.
26.Ang, S.F., et al., A preliminary study to evaluate the strategy of combining clinical criteria and next generation sequencing (NGS) for the identification of monogenic diabetes among multi-ethnic Asians. Diabetes Res Clin Pract, 2016. 119: p. 13-22.
27.Jap, T.S., et al., A novel mutation in the hepatocyte nuclear factor-1alpha/MODY3 gene in Chinese subjects with early-onset Type 2 diabetes mellitus in Taiwan. Diabet Med, 2000. 17(5): p. 390-3.
28.Wu, I.L., Establish The Mode of The Genetic Counseling in Maturity-Onset Diabetes of The Young in Taiwan. Master thesis, National Taiwan university, Graduate institude of molecular medicine, 2007.
29.Liao, M.H., Genetic and clinical characteristics of Taiwan maturity-onset diabetes of the young (MODY) patients. Master thesis, National Taiwan university, Graduate institude of molecular medicine. 2010.
30.Fajans, S.S., G.I. Bell, and K.S. Polonsky, Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med, 2001. 345(13): p. 971-80.
31.Gloyn, A.L., et al., Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med, 2004. 350(18): p. 1838-49.
32.Giacomo Lanzoni, C.R., Luca Inverardi, and Juan Domı ́nguez-Bendala, Pancreatic Islet Regeneration: The Developmental and Stem Cell Biology Approach. Regenerative Medicine Applications in Organ Transplantation., 2014. 42: p. 609-625.
33.Meur, G., et al., Insulin gene mutations resulting in early-onset diabetes: marked differences in clinical presentation, metabolic status, and pathogenic effect through endoplasmic reticulum retention. Diabetes, 2010. 59(3): p. 653-61.
34.Huang, K., et al., How insulin binds: the B-chain alpha-helix contacts the L1 beta-helix of the insulin receptor. J Mol Biol, 2004. 341(2): p. 529-50.
35.Ryu, J., et al., APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Cell Rep, 2014. 7(4): p. 1227-38.
36.Saito, T., et al., The interaction of Akt with APPL1 is required for insulin-stimulated Glut4 translocation. J Biol Chem, 2007. 282(44): p. 32280-7.
37.Wang, C., et al., Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function. Diabetologia, 2013. 56(9): p. 1999-2009.
38.Hardt, P.D., et al., High prevalence of exocrine pancreatic insufficiency in diabetes mellitus. A multicenter study screening fecal elastase 1 concentrations in 1,021 diabetic patients. Pancreatology, 2003. 3(5): p. 395-402.
39.Tattersall, R.B. and S.S. Fajans, A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes, 1975. 24(1): p. 44-53.
40.Barrio, R., et al., Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. J Clin Endocrinol Metab, 2002. 87(6): p. 2532-9.
41.Johansen, A., et al., Half of clinically defined maturity-onset diabetes of the young patients in Denmark do not have mutations in HNF4A, GCK, and TCF1. J Clin Endocrinol Metab, 2005. 90(8): p. 4607-14.
42.Furuta, H., et al., Organization and partial sequence of the hepatocyte nuclear factor-4 alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY. Diabetes, 1997. 46(10): p. 1652-7.
43.Pearson, E.R., et al., Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med, 2007. 4(4): p. e118.
44.Rubio-Cabezas, O., et al., ISPAD Clinical Practice Consensus Guidelines 2014. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes, 2014. 15 Suppl 20: p. 47-64.
45.Vionnet, N., et al., Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature, 1992. 356(6371): p. 721-2.
46.Vits, L., et al., Identification of novel and recurrent glucokinase mutations in Belgian and Luxembourg maturity onset diabetes of the young patients. Clin Genet, 2006. 70(4): p. 355-9.
47.Pinterova, D., et al., Six novel mutations in the GCK gene in MODY patients. Clin Genet, 2007. 71(1): p. 95-6.
48.Shen, Y., et al., Insight into the biochemical characteristics of a novel glucokinase gene mutation. Hum Genet, 2011. 129(3): p. 231-8.
49.Osbak, K.K., et al., Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat, 2009. 30(11): p. 1512-26.
50.Ellard, S., Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) mutations in maturity-onset diabetes of the young. Hum Mutat, 2000. 16(5): p. 377-85.
51.Yamada, S., et al., Mutations in the hepatocyte nuclear factor-1alpha gene (MODY3) are not a major cause of late-onset NIDDM in Japanese subjects. Diabetes, 1997. 46(9): p. 1512-3.
52.Yoshiuchi, I., et al., Three new mutations in the hepatocyte nuclear factor-1alpha gene in Japanese subjects with diabetes mellitus: clinical features and functional characterization. Diabetologia, 1999. 42(5): p. 621-6.
53.Murphy, R., S. Ellard, and A.T. Hattersley, Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab, 2008. 4(4): p. 200-13.
54.Macfarlane, W.M., et al., Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes. J Clin Invest, 1999. 104(9): p. R33-9.
55.Fajans, S.S., et al., Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60. Transl Res, 2010. 156(1): p. 7-14.
56.Bellanné-Chantelot, C., et al., Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med, 2004. 140(7): p. 510-7.
57.Edghill, E.L., et al., Mutations in hepatocyte nuclear factor-1beta and their related phenotypes. J Med Genet, 2006. 43(1): p. 84-90.
58.Torsvik, J., et al., Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes. Hum Genet, 2010. 127(1): p. 55-64.
59.Yan, J., et al., Whole-exome sequencing identifies a novel INS mutation causative of maturity-onset diabetes of the young 10. J Mol Cell Biol, 2017. 9(5): p. 376-383.
60.Boesgaard, T.W., et al., Further evidence that mutations in INS can be a rare cause of Maturity-Onset Diabetes of the Young (MODY). BMC Med Genet, 2010. 11: p. 42.
61.Piccini, B., et al., Clinical and molecular characterization of a novel INS mutation identified in patients with MODY phenotype. Eur J Med Genet, 2016. 59(11): p. 590-595.
62.Johnson, S.R., et al., Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism. Pediatr Diabetes, 2018.
63.Dusatkova, L., et al., Frameshift mutations in the insulin gene leading to prolonged molecule of insulin in two families with Maturity-Onset Diabetes of the Young. Eur J Med Genet, 2015. 58(4): p. 230-4.
64.Yorifuji, T., et al., The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus. J Clin Endocrinol Metab, 2005. 90(6): p. 3174-8.
65.Bingham, C. and A.T. Hattersley, Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factor-1beta. Nephrol Dial Transplant, 2004. 19(11): p. 2703-8.
66.Agladioglu, S.Y., et al., Maturity onset diabetes of youth (MODY) in Turkish children: sequence analysis of 11 causative genes by next generation sequencing. J Pediatr Endocrinol Metab, 2016. 29(4): p. 487-96.
67.Ellard, S., et al., Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. Diabetologia, 2013. 56(9): p. 1958-63.
68.Alkorta-Aranburu, G., et al., Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach. Mol Genet Metab, 2014. 113(4): p. 315-320.
69.Warr, A., et al., Exome Sequencing: Current and Future Perspectives. G3 (Bethesda), 2015. 5(8): p. 1543-50.
70.Technologies, A., SureSelectXT Target Enrichment System for Illumina Paired-End Multiplexed Sequencing Library. 2017 Version C1.
71.Aaron McKenna, M.H., 1 Eric Banks,1 Andrey Sivachenko,1 Kristian Cibulskis,1 Andrew Kernytsky,1 Kiran Garimella,1 David Altshuler,1,2 Stacey Gabriel,1 Mark Daly,1,2 and and Mark A. DePristo1, The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Research, 2010. 20: p. 1297-1303.
72.Adzhubei, I.A., et al., A method and server for predicting damaging missense mutations. Nat Methods, 2010. 7(4): p. 248-9.
73.Adzhubei, I., D.M. Jordan, and S.R. Sunyaev, Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet, 2013. Chapter 7: p. Unit7 20.
74.Flannick, J., S. Johansson, and P.R. Njolstad, Common and rare forms of diabetes mellitus: towards a continuum of diabetes subtypes. Nat Rev Endocrinol, 2016. 12(7): p. 394-406.
75.R Development Core Team (2008). R: A language and environment for
statistical computing. R Foundation for Statistical Computing,
Vienna, Austria. ISBN 3-900051-07-0, URL http://www.r-project.org/.2008.
76.Thorvaldsdottir, H., J.T. Robinson, and J.P. Mesirov, Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform, 2013. 14(2): p. 178-92.
77.Ewing, B. and P. Green, Base-calling of automated sequencer traces using phred. II. Error probabilities. Genome Res, 1998. 8(3): p. 186-94.
78.Richards, S., et al., Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med, 2015. 17(5): p. 405-24.
79.Clark, M.J., et al., Performance comparison of exome DNA sequencing technologies. Nat Biotechnol, 2011. 29(10): p. 908-14.
80.Sims, D., et al., Sequencing depth and coverage: key considerations in genomic analyses. Nat Rev Genet, 2014. 15(2): p. 121-32.
81.Lin, D.C., Detecting the Mutations of Neonatal Diabetes and Type 1B Diabetes Using Exome Sequencing and Analysis of Mutant Glucokinase Activity. Master thesis, Mackay medical college, Institude of biomedical sciences, http://handle.ncl.edu.tw/11296/3d49rb, 2015.
82.Ivarsson, S.A. and A. Lernmark, Comment on: Edghill et al. (2008) Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood: Diabetes 57:1034-1042, 2008. Diabetes, 2008. 57(5): p. e9.
83.Kamata, K., et al., Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase. Structure, 2004. 12(3): p. 429-38.
84.Shammas, C., et al., A report of 2 new cases of MODY2 and review of the literature: implications in the search for type 2 diabetes drugs. Metabolism, 2013. 62(11): p. 1535-42.
85.Barbetti, F., et al., Opposite clinical phenotypes of glucokinase disease: Description of a novel activating mutation and contiguous inactivating mutations in human glucokinase (GCK) gene. Mol Endocrinol, 2009. 23(12): p. 1983-9.
86.Fred P. Ernani, E.M.L., Agilent’s SureSelect Target Enrichment System:Bringing Cost and Process Efficiency to Next-Generation Sequencing(Product Note). Agilent Technologies, Inc. Santa Clara, USA, 2016.
87.Waterhouse, A., et al., SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res, 2018. 46(W1): p. W296-W303.
88.Vaxillaire, M. and P. Froguel, Monogenic diabetes in the young, pharmacogenetics and relevance to multifactorial forms of type 2 diabetes. Endocr Rev, 2008. 29(3): p. 254-64.
89.McCarthy, M.I. and A.T. Hattersley, Learning from molecular genetics: novel insights arising from the definition of genes for monogenic and type 2 diabetes. Diabetes, 2008. 57(11): p. 2889-98.
90.Yorifuji, T., et al., Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus. Pediatr Diabetes, 2012. 13(1): p. 26-32.
91.Johnson, S.R., et al., A novel INS mutation in a family with maturity-onset diabetes of the young: Variable insulin secretion and putative mechanisms. Pediatr Diabetes, 2018. 19(5): p. 905-909.
92.Fox, E.J., et al., Accuracy of Next Generation Sequencing Platforms. Next Gener Seq Appl, 2014. 1.
93.Quail, M.A., et al., A tale of three next generation sequencing platforms: comparison of Ion Torrent, Pacific Biosciences and Illumina MiSeq sequencers. BMC Genomics, 2012. 13: p. 341.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top