ANDROGEN METABOLISM IN CHILDHOOD

我们计划调查由类固醇引起的先天性肾上腺增生症 皮质醇生物合成缺陷--21-羟基酶缺乏症 遗传为常染色体隐性遗传，与人类白细胞抗原相关 组织相容性复合体。这是这种疾病的一种轻微变体， “非经典”(NC)21-OHD是最常见的人类常染色体 隐性疾病，症状包括多毛症和不孕症。我们 建议在高危民族人群中进行筛查，以确认 目前对这种疾病频率的高估计，并提供了一个 适合本病自然病史的患者人群 可能会被前瞻性地研究。这可能会对 关于患有这种疾病的个体的治疗决定。三分之二 患有更严重的21-OHD的患者中 醛固酮生物合成的额外缺陷可能导致 盐耗、休克和死亡，尤其是在新生儿期。我们会 研究等位基因在决定盐分浪费中的作用 表型。我们还将研究可能影响 已经恢复合成能力的个体的盐分浪费 醛固酮，以及具有21-OHD的人类白细胞抗原相合的同胞 不和谐的盐分浪费。正常的“21-OHase B”基因，它编码一个 细胞色素P450是一种细胞色素P450，已被分离和鉴定。 经典的21-OHD等位基因中有四分之一是该基因的缺失。 导致不同形式的21-OHD的非缺失突变基因将是 从携带21-OHase杂合缺失的个体中分离出来 B基因。每个突变都将通过DNA测序进行识别，当 通过对序列的检查，突变的影响并不明显， 突变基因将通过导入肾上腺皮质细胞来表达 排队。因此，每个突变基因的功能可以与 临床表现。这将为评估提供一种新的模式 对这种常见病，尤其适用于产前诊断。

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.