ANDROGEN METABOLISM IN CHILDHOOD

我们计划调查先天性肾上腺皮质增生由于类固醇 21-羟化酶缺乏症（21-OHD），皮质醇生物合成缺陷 作为常染色体隐性遗传性状遗传，与HLA主要 组织相容性复合体 这种疾病的一种轻微变种， “非经典”（NC）21-OHD，是人类常染色体显性遗传中最常见的一种。 隐性疾病，症状包括多毛症和不育症。 我们 建议在高风险种族人群中进行筛查，以确认 目前对这种疾病的频率估计很高，并提供一个 适合的患者人群，其中这种疾病的自然史 可以进行前瞻性研究。 这可能会产生重大影响， 治疗决定与这种疾病的个人。 三分之二 患有更严重的“经典”形式的21-OHD的患者中， 醛固酮生物合成中的另外缺陷， 盐耗、休克和死亡，尤其是在新生儿期。 我们将 研究等位基因在确定盐耗中的作用 表型。 我们还将研究表观遗传因素， 盐浪费的人谁已经恢复了合成能力， 醛固酮，而在HLA相同的同胞与21-OHD谁，但 不一致的盐浪费。 正常的“21-OHase B”基因，其编码 特异性细胞色素P450，以前已经分离和表征。 四分之一的经典21-OHD等位基因是该基因的缺失。 负责不同形式的21-OHD的非缺失突变基因将被 分离自携带21-OH酶杂合缺失的个体 B基因。 每一个突变都将通过DNA测序来鉴定，当 突变的影响从序列的检查中不明显， 突变基因将通过转染到肾上腺皮质细胞中来表达 线 因此，每个突变基因的功能可以与 临床表现 这将为评价提供一种新的模式 这一常见病，特别适用于产前诊断。

We plan to investigate congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency (21-OHD), a defect of cortisol biosynthesis inherited as an autosomal recessive trait linked to the HLA major histocompatibility complex. A mild variant of this disorder, "non-classical" (NC) 21-OHD, is among the most common human autosomal recessive diseases, with symptoms including hirsutism and infertility. We propose a screening program in a high risk ethnic population to confirm the present high estimates of the frequency of this disorder, and to provide a suitable patient population in which the natural history of this disorder may be prospectively studied. This is likely to have significant impact on therapeutic decisions regarding individuals with this disorder. Two thirds of patients with the more severe "classical" form of 21-OHD have an additional defect in aldosterone biosynthesis which can result in salt-wasting, shock and death, especially in thee neonatal period. We will investigate the role of allelism in determining the salt-wasting phenotype. We will also examine epigenetic factors which might influence salt-wasting in individuals who have recovered the capacity to synthesize aldosterone, and in HLA-identical sibs with 21-OHD who are nevertheless discordant for salt-wasting. The normal "21-OHase B" gene, which encodes a specific cytochrome P450, has previously been isolated and characterized. One-fourth of classical 21-OHD alleles are deletions of this gene. Non-deleted mutant genes responsible for different forms of 21-OHD will be isolated from individuals who carry a heterozygous deletion of the 21-OHase B gene. Each mutation will be identified by DNA sequencing, and, when the effect of a mutation is not apparent from inspection of the sequence, the mutant gene will be expressed by transfection into an adrenocortical cell line. Thus, the functioning of each mutant gene can be correlated with clinical presentation. This will provide a new modality for the evaluation of this common disease, particularly applicable to prenatal diagnosis.