偽副甲狀腺低下症Ia型的基因檢測與遺傳諮詢

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。

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 .