Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency
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DOI：
10.1210/jc.86.1.207
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发表时间：
2001-01-01
影响因子：
5.8
通讯作者：
Kuttenn, F
中科院分区：
文献类型：
--
作者：
Deneux, C;Tardy, V;Kuttenn, F
对 56 名患有症状性非典型先天性肾上腺增生症的无亲属关系的法国女性进行了 CYP21 基因的完整分析。检查了突变谱和表型-基因型相关性。总体主要突变是 V281L，该突变存在于 51% 的等位基因和 80% 的女性中。发现了三个新突变：L317M、R435C 和 5' 端基因转换。 63% 的女性携带 CYP21 基因的严重突变，因此有可能生下患有该疾病典型形式的孩子。在这种情况下，筛查伴侣的杂合性至关重要。根据 CYP21 等位基因组合将患者分为三组，检查潜在的基因型/表型相关性：A（轻度/轻度）、B（轻度/重度）和 C（重度/重度）。与具有两种轻度突变的女性（A组）相比，轻度和重度突变的复合杂合子（B组）原发性闭经更频繁，平均基础和刺激17-羟基孕酮水平较高，但个体值有相当大的重叠。令人惊讶的是，在两名女性中，两个等位基因（C 组）均发现了严重突变。因此，不能从基因型准确预测表型。表型表达的变异可能受到 CYP21 基因座遗传异质性以外的机制的影响。
Complete analysis of the CYP21 gene was performed in 56 unrelated French women with symptomatic nonclassical congenital adrenal hyperplasia. The mutational spectrum and the phenotype-genotype correlation were examined. The overall predominant mutation was V281L, which was present on 51% of alleles and in 80% of women. Three novel mutations were found: L317M, R435C, and a 5'-end gene conversion. Sixty-three percent of the women were carrying a severe mutation of the CYP21 gene, and hence risk giving birth to children with a classical form of the disease. In such cases, screening for heterozygosity in the partner is crucial. Potential genotype/phenotype correlations were examined by classifying the patients into three groups according to the CYP21 allelic combinations: A (mild/mild), B (mild/severe), and C (severe/severe). Primary amenorrhea was more frequent, and mean basal and stimulated 17-hydroxyprogesterone levels were higher in compound heterozygotes for mild and severe mutations (group B) compared with women with two mild mutations (group A), but there was a considerable overlap for individual values. Surprisingly, in two women, a severe mutation was found on both alleles (group C). Therefore, the phenotype cannot be accurately predicted from the genotype. Variability in phenotypic expression may be conditioned by mechanisms other than genetic heterogeneity at the CYP21 locus.