- 期刊
Molecular Identification of Combined Homozygous and Compound Heterozygous Mutations in the CYP21 Gene in Simple Virilizing Congenital Adrenal Hyperplasia in Taiwan
台灣非鹽分漏失型先天性腎上腺增生症的合併型同合子有複合型異合子的分子生物學研究
摘要
先天性腎上腺增生症是一種常染色體隱性遺傳病，其分子生物學的致病機轉在於CYP21基因發生突變所造成。我們的研究室使用ACRS/SSCP的方法。分析十年來收集的85個病例，其非血親通婚的父母及其手足，結果發現在台灣常見的CYP21基因的Intron 2的突變，其次依次爲exon 8,4,3等。應爲單純合子突變。我們特挑出兩個及臨床上均證實爲非鹽分漏失型先天性腎上腺增生症，但經過分子生物學分析發現，第一類共4個非血親通婚家族是起因於雙新均爲Intron 2(nt656)及8-bp突變，病人乃成爲Int 2(nt656)/8-bp合併型同合子突變。另一類11個非血親通婚家庭起因於父親codon 172突變，母親intron 2(nt656)突所造成的codon 172pat/int 2(nt656)mat複合型雜合子突變。由吾等大規模的分子生物學研究發現，常染色體隱性遺傳病像這種單純男性化的先天性腎上腺增生症可起因於合併型同合子突變，亦可起因於複合型雜合子突變。 吾等將繼續對鹽分漏失型的先天性腎上腺增生症做分子生物學的探討，並與本研究相對照，以便做更進一步的基因型/表現型的探討。
並列摘要
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder mainly caused by defects in the steroid 21-hydroxylase (CYP2J) gene. We have experience of molecular analysis of in the CYP21 gene in 85 unrelated CAH families, in Taiwan for ten years. All ten exons of were analyzed by differential polymerase chain reactions (PCR) followed by single-strand conformation polymorphism (SSCP) analysis and the amplification-created restriction site (ACRS) method. More than 90% of the mutations were due to conversion of DNA sequences into its neighboring homologous pseudo gene CYP21P. The most frequent mutation found in CAH patients in Taiwan was intron 2 mutation; the others were exons 8, 4 and 3, respectively, decreasing by frequency. Those were single homozygous mutations. In this report, we present two kinds of special mutations in our molecular research. Four families had their babies coming from combined homozygous mutation of both parents, that is due to both intron 2 (nt656) and 8-bp mutation. Eleven families had their babies coming from paternal codon 172 and maternal intron 2 (nt656) compound heterozyous mutations, that is codon 172 pat/int 2 (nt656) mat mutation. These two mutations had clinical manifestation of virilization, that is, enlarged clitoris only, but neither clinical nor laboratory finding of salt-losing. From our study, we found that autosomal recessive disorders such as simple virilizing CAH in our series could result from either combined homozygous mutations or compound heterozygous mutations. Further molecular study will focus on the salt-losing type in order to correlate the genotype/phenotype with this study.