請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37355完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊偉勛(Yang Wei-Shiung) | |
| dc.contributor.author | Guo-Mei Pan | en |
| dc.contributor.author | 潘國美 | zh_TW |
| dc.date.accessioned | 2021-06-13T15:25:22Z | - |
| dc.date.available | 2008-08-14 | |
| dc.date.copyright | 2008-08-14 | |
| dc.date.issued | 2008 | |
| dc.date.submitted | 2008-07-18 | |
| dc.identifier.citation | 1. Murat Bastepe, Harald Juppner. 2005 GNAS Locus and Pseudohypoparathyroidism. Horm Res. 63:65-74
2. W. Ahrens, O. Hiort, P. Staedt, T. Kirschner, C. Marschke, K. Kruse. 2001 Analysis of the GNAS1 Gene in Albright ’s Hereditary Osteodystrophy . J Clin Endocrinol Metab. 86(10):4630-4634 3. G. Mantovani, R. Romoli, G. Weber, V. Brunelli, E. De Menis, S. Beccio, P. Beck-Peccoz, A. Spada. 2000 Mutational Analysis of GANS1 in Patients with Pseudihypoparathyroidism : Identification of Two Novel Mutations. J Clin Endocrinol Metab. 85:4243-4248 4. Lee S. Weinstein, Jie Liu, Akio Sakamoto, Tao Xie, Min Chen. 2004 Minireview : GNAS : Normal and Abnormal Functions. Endocrinology. 145(12):5459-5464 5. Allen M. Spiegel and Lee S. Meinstein. 2004 Inherited Diseases Involving G Proteins And G Protein-Coupled Receptors. Annu. Rev. Med. 55:27-39 6. Micheala A Aldred and Richard D Trembath. 2000 Activating and Inactivating Mutations in the GNAS1 Gene. Hum Mutat. 16(3):183-9. 7. ACF Lam, DHC Chan, KKS Lai, TMF Tong, IFM Lo, STS Lam. 2006 Phenotypic Spectrum of 3 Pseudohypoparathyroidism type 1a, and 2 Pseudopseudohypoparathyroidism Chinese Patients with Novel GNAS Mutations. HK J Paediatr (New Series) 11:284-289 8. Alexander Miric, Janet D. Vechio, Michael A. Levine. 1993 Heterogeneous Mutations in the Gene Encoding the α-subunit of the Stimulatory G Protein of Adenylyl Cyclase in Albright Hereditary Osteodystrophy. J Clin Endocrinol Metab. 76:1560-1568 9. WF Schwindinger, A Miric, D Zimmerman and MA Levine. 1994 A novel Gs alpha mutant in a patient with Albright hereditary osteodystrophy uncouples cell surface receptors from adenylyl cyclase . Biol. Chem. 269: 25387-25391 10. Zvi Farfel, Taroh Iiri, Hagit Shapira, Abraham Roitman, Meir Mouallem and Henry R. Bourne. 1996 Pseudohypoparathyroidism, a Novel Mutation in the -Contact Region of Gsα Impairs Receptor Stimulation. J Biol Chem. 33:19653-5 11. Yuichi Ishikawa, Toshihiro Tajima, Jun Nakae, Tetsuro Nagashima. 2001 Two mutations of the Gsα gene in two Japanese patients with sporadic pseudohypoparathyroidism type Ia. J Hum Genet 46:426-430 12. AGNES LINGLART, JEAN CLAUDE CAREL, MICHELE GARABEDIAN. 2002 GNAS1 Lesions in Pseudohypoparathyroidism Ia and Ic:Genotype Phenotype Relationship and Evidence of the Maternal Transmission of the Hormonal Resistance. J Clin Endocrinal Metab 87:189-197 13. J. A. Fischer, F. Egert, E. Werder and W. Born. 1998 An Inherited Mutation Associated with Functional Deficiency of the -Subunit of the Guanine Nucleotide-Binding Protein Gs in Pseudo- and Pseudopseudohypoparathyroidism. J Clin Endocrinol Metab. 1998 Mar;83(3):935-8 14. Iiri, Taroh , Herzmark, Paul; Nakamoto, Jon M . 1994 Rapid GDP release from Gsα in patients with gain and loss of endocrine function. Nature 371:164-168. 15. L S Weinstein, P V Gejman, E Friedman, T Kadowaki, R M Collins, E S Gershon, and A M Spiegel. 1990 Mutations of the Gs alpha-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc Natl Acad Sci U S A. 21: 8287–8290. 16. Albright F, Burnett CH, Smith CH. 1942 Pseudohypoparathyroidism:an example of Sebright-Bantam syndrome. Endocrinology 30:922-932. 17. Tashjian AH, Frantz AG and Lee JB. 1966 Pseudohypoparathyroidism:assays of parathyroid hormone and thyrocalcitonin. Proceedings of the National Academy of Sciences of the USA. 56:1138-1142. 18. Mann JB, Alterman S and Hills AG. 1962 Albright’s Hereditary osteodystrophy comprising pseudohypoparathyrodism and pseudopseudohypoparathyroidism with a report of two cases representing the complete syndrome occurring in successive generation. Annals of Internal Medicine 56:315-342. 19. LAN Wei, ZHANG Fan, DAI Ya-li, LIU Jian-min, SUN Li-hao, ZHAO Hong-yan, SUI Bin, NING Guang. 2006 The study of pseudohypoparathyroidism type Ia and a mutation of GNAS1：a family report. 20. Wtinstein LS, Gejman PV, Mazancorte P de, American N, Spiegel AM. 1992 A heterozygous 4-bp deletion mutation in the Gsα gene ( GNAS1 ) in a patient with Albright hereditary osteodystrophy. Genomics 13:1319-1321. 21. Shuhua Yu, Dawen Yu, Bryan E. Halnline, Jacob L. Brener. 1995 A deletion hot-spot in exon 7 of the Gsα gene ( GNAS1 ) in patients with Albright hereditary osteodystrophy. Human Molecular Genetics 10:2001-2002. 22. Monique E. M. Oude Luttikhuis, Louise C. Wilson, James V. Leonard and Richard C. Trembath. 1994 Characterization of a de novo 43-bp Deletion of the Gsα gene ( GNAS1 ) in Albright Hereditary Osteodystrophy. Genomics 21:455-457. 23. Aldred MA, Trembath RC. 2000 Activating and inactivating mutations in the human GNAS1 gene. Hum Mutat. 16(3):183-9. 24. Giovanna Mantovani. 2006 Mutations in the Gs alpha gene causing hormone resistance. Best practice & research clinical endocrinology & metabolism 20:501-513. 25. Tashjian AH, Frantz AG & Lee JB. 1966 Pseudohypoparathyroidism:assays of parathyroid hormone and thyrocalcitonin. Proceedings of the National Academy of Sciences of the USA 56:1138-1142. 26. Gilchrist A, Bunemann M, Li A, Hosey MM, Hamm HE. 1999 A dominant negative strategy for studying roles of G proteins in vivo. J Biol Chem 274:6610-6616 27. Albright F, Forbes AP & Henneman PH. 1952 Pseudopseudohypoparathyroidism. Transactions of the Association of American Physicians 65:337-350. 28. Hayward B, Barlier A, Korbonits M, Grossman A, Jacquet P, Enjalbert A, Bonthron D. 2001 Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly. J Clin Invest 107 : R31-R36. 29. Warner D. R, Gejman P. V, Collins R. M, Weinstein, L. S. 1997 A novel mutation adjacent to the switch III domain of Gs-alpha in a patient with pseudohypoparathyroidism. Molec. Endocr. 11: 1718-1727 30. Susanne T, Ralf W, Wiebke A, Ute H, Christine M, Pia S, Olaf H. 2007 A Disruptive Mutation in Exon 3 of the GNAS Gene with Albright Hereditary Osteodystrophy, Normocalcemic Pseudohypoparathyroidism, and Selective Long Transcript Variant Gsα-L Deficiency. J Clin Endocrinol Metab. 92(5):1764-1768 31. Joachim P, Wiebke A, and Olaf H. 2003 A new heterozygous mutation (L338N) in the human Gsα ( GNAS1) gene as a cause for congenital hypothyroidism in Albright’s Hereditary Osteodystrophy. European Journal of Endocrinology 148:463-468 32. HAGIT SHAPIRA, EITAN FRIEDMAN, MEIR MOUALLEM, and ZVI FARFEL. 1996 Familial Albright’s Hereditary Osteodystrophy with Hypoparathyroidism: Normal Structural Gsα Gene. J Clin Endocrinol Metab. 81(4):1660-1662 33. Murat Bastepe, Leopold F. Frohlich, Geoffrey N. Hendy, Olafur S. Indridason, Robert G. Josse, Hiroyuki Koshiyama, Jarmo Korkko, Jon M. Nakamoto, Arlan L. Rosenbloom, Arnold H. Slyper, Toshitsugu Sugimoto, Agathocles Tsatsolis, John D. Crawford, and Harald Juppner. 2003 Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS. J. Clin. Invest. 112:1255-1263 34. Spiegel AM, Shenker A & Weinstein LS. 1992 Receptor-effector coupling by G proteins: implications for normal and abnormal signal transduction. Endocrine Reviews 13:536-565 35. Dhanasekaran N, Heasley LE & Johnson GL. 1995 G protein-coupled receptor systems involved in cell growth and oncogenesis. Endocrine Reviews 16:259-270 36. Spiegel AM. 1996 Mutations in G proteins and G protein-coupled receptors in endocrine disease. The Journal of Clinical Endocrinology and Metabolism 81:2434-2442 37. Farzel A, Bournel HR & Tahor I. 1999 The expanding spectrum of G protein diseases. The New England Journal of Medicine 340:1012-1019 38. Lania A, Mantovani G & Spada A. 2001 G protein mutations in endocrine diseases. European Journal of Endocrinology 145:543-559 39. Spada A, Vallar L & Faglia G. 1992 G protein oncogene in pituitary tumors. Trends in Endocrinology and Metabolism 3:355-360 40. Wettschureck N & Offermanns S. 2005 Mammalian G proteins and their cell type specific functions. Physiological Reviews 85:1159-1204 41. Dryja TP, Hahn LB, Reboul T et al. 1996 Missense mutation in the gene encoding the alpha subunit of rod transducin in the Nougaret form of congenital stationary night blindness. Nature Genetics 13:358-360 42. Peters J, Wroe SF. Wells CA, Miller HJ, Bodle D, Beechey CV, Williamson CM, Kelsey G. 1999 A cluster of oppositely imprinted transcripts at the Gnas locus in the distal imprinting region of mouse chromosome 2. Proc Natl Acad Sci USA 96:3830-3835 43. Hayward B, Kamiya M, Strain L, Moran V, Campbell R, Hayashizaki Y, Bronthon DT. 1998 The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc Natl Acad Sci USA 95:10038-10043. 44. Kehlenbach RH, Matthey J, Huttner WB.1994 XLαs is a new type of G protein. Nature 372:804-809. (1995 Erratum in Nature 375:253) 45. Ischia R, Lovisetti-Scamihorn P, Hogue-Angeletti R, Wolkersdorfer M, Winkler H, Fischer-Colbrie R. 1997 Molecular cloning and characterization of NESP55, a novel chromogranin-like precursor of a peptide with 5-HT1B receptor antagonist activity. J Biol Chem 272:11657-11662. 46. Hayward BE, Moran V, Strain L, Bonthron DT. 1998 Bidirectional imprinting of a single gene:GNAS1 encodes maternally, paternally, and biallelically derived proteins. Proc Natl Acad Sci USA 95:15475-15480. 47. Swaroop A, Agarwal N, Grucn JR, Bick D, Weissman SM. 1991 Differential expression of novel Gs alpha signal transduction protein cDNA species. Nucleic Acids Res 19:4725-4729 48. Liu J, Yu S, Litman D, Chen W, Weinstein L. 2000 Identification of a methylation imprint mark within the mouse gnas locus. Mol Cell Biol 20:5808-5817 49. Ishikawa Y, Bianchi C, Nadal-Ginard B, Homcy CJ. 1990 Alternative promoter and 5’ exon generate a novel Gsα mRNA. J Biol Chem 265:8458-8462 50. Hayward B, Bonthron D. 2000 An imprinted antisense transcript at the human GNAS1 locus. Hum Mol Genet 9:835-841 51. Wroe SF, Kelsey G, Skinner JA, Bodle D, Ball ST, Beechey CV, Peters J, Williamson CM. 2000 An imprinted transcript, antisense to Nesp, adds complexity to the cluster of imprinted genes at the mouse Gnas locus. Proc Natl Acad Sci USA 97:3342-3346 52. Chase LR, Melson GL, Aurbach GD. 1969 Pseudohypoparathyroidism:Defective excretion of 3’,5’-AMP in response to parathyroid hormone. J Clin Invest 48:1832-1844 53. Drezner M, Neelon FA, Lebovitz HE. 1973 Pseudohypoparathyroidism type II:A possible defect in the reception of the cyclic AMP signal. N Engl J M ed 289:1056-1060 54. Levine MA. 2002 Pseudohypoparathyroidism;in Bilezikian JP, Raisz LG, Rodan GA(cds). Principles of Bone Biology. New York, Academic Press 1137-1163 55. Weinstein LS, Yu S, Warner DR, Liu J. 2001 Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Endocr Rev 22:675-705 56. Davies AJ, Hughes HE. 1993 Imprinting in Albright’s hereditary osteodystrophy. J Med Genet 30:101-103 57. Wilson LC, Oude-Luttikhuis MEM, Clayton PT, Fraser WD, Trembath RC. 1994 Parental origin of Gsα gene mutations in Albright’s hereditary osteodystrophy. J Med Genet 31:835-839 58. Kaplan FS, Shore EM. 2000 Progressive osseous heteroplasia. J Bone Miner Res 15:2084-2094 59. Eddy MC, De Beur SM, Yandow SM, McAlister WH, Shore EM, Kaplan FS, Whyte MP, Levine MA. 2000 Deficiency of the alpha-subunit of the stimulatory G protein and severe extraskeletal ossification. J Bone Miner Res 15:2074-2083 60. Shore EM, Ahn J, Jan de Beur S, Li M, Xu M, Gardner RJ, Zasloff MA, Whyte MP, Levine MA, Kaplan FS. 2002 Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med 346:99-106 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37355 | - |
| dc.description.abstract | 偽副甲狀腺低下症 ( Pseudohypoparathyroidism = PHP ) 是一種標的器官對副甲狀腺素 ( PTH ) 產生抗性而導致低血鈣高血磷的體染色體顯性遺傳性疾病，偽副甲狀腺低下症Ia型 ( Pseudohypoparathyroidism-Ia = PHP-Ia )是PHP中最常見的一種分型，除了對副甲狀腺素有抗性，並對於其他與Gsα蛋白結合而活化adenylyl cyclase的荷爾蒙也會產生抗性，因此PHP-Ia病人血中副甲狀腺素和其他相關荷爾蒙會升高，同時伴隨著典型的AHO ( 以下症狀集合稱之 : 身材矮小 、 圓臉 、 短指症、異位型骨化、心智障礙等 ) 。已知PHP-Ia發病原因主要是因為染色體20q13.11位置上Gsα蛋白基因 ( Guanine Nucleotide binding protein Alpha Stimulating activity polypeptide 1; GNAS1) 有異型合子的缺陷，導致Gsα蛋白的表現異常和活性功能減低，目前發表過的文獻，在德國、義大利、美國、英國、香港和日本等國，已有超過50個不同的突變點被找到，超過七成的病患可以在GNAS1基因上發現到突變點，另外三成病患的分子病理機轉尚不明確。
在此篇論文中，共收集了分別來自於不同家族的3位PHP-Ia個案和一個PHP-Ia家庭，針對GNAS1基因的13個外顯子 ( exons ) 進行分析，其中在一個家庭的外顯子5，發現一個異型合子的置換突變 ( heterozygous missense mutation )，會造成胺基酸的改變，使得密碼子106 ( codon 106 ) 原本是異白胺酸 ( Isoleucine) 的位置變成息寧胺酸 ( Threonine ) ，這是台灣地區目前初次在PHP-Ia 病人身上找到突變，也是一個全新未在國際上發表過的突變，希望以此研究作為基礎，建立PHP-Ia的基因檢測與遺傳諮詢平台模式，提供病人專業協助與諮商。 | zh_TW |
| dc.description.abstract | Pseudohypoparathyroidism is an autosomal dominant disease characterized by hypocalcemia and hyperphosphatemia duo to target-organ resistance to parathyroid hormone (PTH). PHP-Ia ( Pseudohypoparathyroidism-Ia ) is the most frequent type of PHP . Patients with PHP-Ia often present with additional hormonal resistance and show characteristic physical features that are collectively termed AHO ( Albright’s hereditary osteodystrophy , a congenital syndrome in which patients develop short stature、round face、obesity、 brachydactyly、heterotopic ossification , and mental retardation ). PHP-Ia is caused by heterozygous inactivating mutations located in GNAS1 gene that mapped to chromosome 20q13.11, which encoding the α subunit of the stimulatory guanine nucleotide-binding protein (Gsα) . They show a partial deficiency of Gs activity and function. To data , over 50 different mutations in GNAS1 have been identified distributed in Germany、Italy、USA、England、Hong Kong and Japan . Regarding molecular analysis , almost seventy percent patients carry detectable GNAS1 mutations , but still thirty unknown so far.
This thesis included three individuals from unrelated families and one PHP-Ia family , Here described the first mutational analysis of GNAS1 in Taiwan PHP-Ia patients , we found a novel heterozygous missense mutation I106T in exon5 , revealed associated with substitution of threonine for isoleucine at codon 106 , the mutation had not been reported previously . Furthermore , we hope set up a model of genetic testing and counseling for PHP-Ia based on this study , contribute highly medical supplyment and consultation in the future . | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T15:25:22Z (GMT). No. of bitstreams: 1 ntu-97-P95448002-1.pdf: 1057628 bytes, checksum: 034f6b5dd64ed8c395b6ee2cd69bceea (MD5) Previous issue date: 2008 | en |
| dc.description.tableofcontents | 目錄
謝誌 1 中文摘要 2 一、 緒論 4 1.1 PHP的起緣 4 1.2 PHP的發生率 13 1.3 PHP臨床表徵與分型 13 1.4 PHP診斷與治療 15 1.5 PHP分子病理機轉 16 1.6 PHP的遺傳模式 16 1.7 研究動機 16 二、 實驗方法與材料 17 2.1 實驗材料 17 2.2 實驗方法 17 三、 結果 20 3.1 家族圖譜 20 3.2 生化檢查 20 3.3 基因型分析 20 四、 討論 21 4.1 突變點 21 4.2 遺傳諮詢 23 五、 結論 25 六、 參考文獻 39 圖 目 錄 Fig 1. PHP classification 26 Fig 2. Molecular mechanism 27 Fig 3. The complex GNAS1 locus. 28 Fig 4. The five main transcripts of GNAS1 gene. 29 Fig 5. PHP-Ia and PPHP 30 Fig 6. Pedigree 31 Fig 7. Sequencing data 32 Fig 8. Heterozygous mutations spread in GNAS1 exon 1~13 33 表目錄 Tab 1. Incidence of signs and symptoms in PHP with AHO. 34 Tab 2. Clinical and molecular features of the different PHP forms 35 Tab 3. Primers and annealing temperature used to amplify the 13 exons of GNAS1 36 Tab 4. GNAS1 mutation in PPHP/PHPIa update 2008 - 1 37 | |
| dc.language.iso | zh-TW | |
| dc.title | 偽副甲狀腺低下症Ia型的基因檢測與遺傳諮詢 | zh_TW |
| dc.title | Genetic Testing and Counseling for Pseudohypoparathyroidism-Ia | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 96-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.coadvisor | 蔡克嵩(Tsai Keh-Sung) | |
| dc.contributor.oralexamcommittee | 李銘仁 | |
| dc.subject.keyword | 偽副甲狀腺功能低下症,低血鈣,Albright遺傳性骨失養症,Gsα蛋白基因, | zh_TW |
| dc.subject.keyword | Pseudohypoparathyroidism,Hypocalcemia,Albright hereditary osteodystrophy = AHO,Guanine Nucleotide binding protein Alpha Stimulating activity polypeptide 1,GNAS1, | en |
| dc.relation.page | 45 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2008-07-21 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| 顯示於系所單位： | 分子醫學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-97-1.pdf 目前未授權公開取用 | 1.03 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。