楊偉勛Wei-Shiung, Yang臺灣大學:分子醫學研究所潘國美Pan, Guo-MeiGuo-MeiPan2010-05-042018-07-092010-05-042018-07-092008U0001-1807200810315500http://ntur.lib.ntu.edu.tw//handle/246246/178657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。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。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. his 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 . urthermore , 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 .目錄誌 1文摘要 2、 緒論 4.1 PHP的起緣 4.2 PHP的發生率 13.3 PHP臨床表徵與分型 13.4 PHP診斷與治療 15.5 PHP分子病理機轉 16.6 PHP的遺傳模式 16.7 研究動機 16、 實驗方法與材料 17.1 實驗材料 17.2 實驗方法 17、 結果 20.1 家族圖譜 20.2 生化檢查 20.3 基因型分析 20、 討論 21.1 突變點 21.2 遺傳諮詢 23、 結論 25、 參考文獻 39 目 錄ig 1. PHP classification 26ig 2. Molecular mechanism 27ig 3. The complex GNAS1 locus. 28ig 4. The five main transcripts of GNAS1 gene. 29ig 5. PHP-Ia and PPHP 30ig 6. Pedigree 31ig 7. Sequencing data 32ig 8. Heterozygous mutations spread in GNAS1 exon 1~13 33目錄ab 1. Incidence of signs and symptoms in PHP with AHO. 34ab 2. Clinical and molecular features of the different PHP forms 35ab 3. Primers and annealing temperature used to amplify the 13 exons of GNAS1 36ab 4. GNAS1 mutation in PPHP/PHPIa update 2008 - 1 37application/pdf1057628 bytesapplication/pdfen-US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PseudohypoparathyroidismHypocalcemiaAlbright hereditary osteodystrophy = AHOGuanine Nucleotide binding protein Alpha Stimulating activity polypeptide 1GNAS1[SDGs]SDG3http://ntur.lib.ntu.edu.tw/bitstream/246246/178657/1/ntu-97-P95448002-1.pdf