Tajima T, Fujieda K, Fujii-Kuriyama Y
Department of Chemistry, Faculty of Science, Tohoku University, Sendai, Japan.
J Clin Endocrinol Metab. 1993 Jul;77(1):86-9. doi: 10.1210/jcem.77.1.8325964.
Over 90% of congenital adrenal hyperplasia (CAH) results from 21-hydroxylase deficiency. Because the CYP21B gene is located within the HLA complex and is very tightly linked to HLA markers, HLA typing is widely used for prenatal diagnosis and identifying heterozygous family members. In the course of a study on identification of heterozygous family members with HLA typing, we recognized an unusual family case in which three siblings share the same HLA haplotype, and only one of them had the simple virilizing form; her two siblings did not have any endocrinological abnormalities. We investigated the mode of genetic transmission by using polymerase chain reaction and single stranded conformation polymorphism. The present study revealed that the proband was a compound heterozygote with the intron 2 mutation that causes aberrant RNA splicing and the missense mutation of exon 4, while the other siblings and the father had only one allele of a missense mutation in exon 4; the mother is a normal homozygote. This result together with DNA fingerprint analysis strongly suggest that the intron 2 mutation occurred de novo in the maternally inherited gene of the proband. This seems to be the first case of a de novo mutation of the CYP21B gene that causes CAH.
超过90%的先天性肾上腺皮质增生症（CAH）由21-羟化酶缺乏引起。由于CYP21B基因位于HLA复合体中，且与HLA标记紧密连锁，HLA分型被广泛用于产前诊断和识别杂合家庭成员。在一项通过HLA分型识别杂合家庭成员的研究过程中，我们发现了一个不寻常的家庭病例，其中三个兄弟姐妹共享相同的HLA单倍型，只有其中一人患有单纯男性化型；她的两个兄弟姐妹没有任何内分泌异常。我们使用聚合酶链反应和单链构象多态性研究了遗传传递模式。本研究表明，先证者是一个复合杂合子，具有导致异常RNA剪接的内含子2突变和外显子4的错义突变，而其他兄弟姐妹和父亲在外显子4中只有一个错义突变等位基因；母亲是正常纯合子。这一结果与DNA指纹分析强烈表明，内含子2突变是在先证者的母系遗传基因中发生的新发突变。这似乎是导致CAH的CYP21B基因新发突变的首例病例。
