Pang Songya, Carbunaru Goldy, Haider Anzar, Copeland Kenneth C, Chang Ying Tai, Lutfallah Chantal, Mason J Ian
Department of Pediatrics, University of Illinois, College of Medicine, Chicago, IL 60612, USA.
Clin Endocrinol (Oxf). 2003 Mar;58(3):323-31. doi: 10.1046/j.1365-2265.2003.01716.x.
We investigated adrenal steroidogenic function relevant to 3beta-hydroxysteroid dehydrogenase (HSD3B2) activity in vivo and HSD3B2 genotype in clinically normal family members of patients with HSD3B2 genotype-proven HSD3B2 deficiency congenital adrenal hyperplasia (CAH) to determine whether genotype-proven carriers for HSD3B2 deficiency exhibit decreased enzyme activity analogous to the mildly decreased adrenal 21-hydroxylase activity in the carriers of CYP21 gene mutation.
DESIGN/PATIENTS: Nineteen adult family members (ages median/range: 37/19-56 years) including 13 females and six males of six unrelated patients with HSD3B2 genotype-proven HSD3B2 deficiency were studied.
All family members had HSD3B2 DNA analysis and an ACTH stimulation test (Cortrosyn 0.25 mg IV bolus) for determination of adrenal HSD3B activity.
Ten of 13 females and five of six males were carriers of a proven or predictably deleterious mutation in one allele of the HSD3B2 gene, which was identified in the probands. ACTH-stimulated levels of 17-hydroxypregnenolone (delta5-17P), 17-hydroxyprogesterone (17-OHP), cortisol (F), dehydroepiandrosterone (DHEA) and androstenedione (delta4-A) and ratios of delta5-17P to 17-OHP, delta5-17P to F and DHEA to delta4-A, as well as increments of delta5-17P and DHEA values (ACTH-stimulated - baseline) in the genotype-proven female carriers (age, mean +/- SD: 36 +/- 6.7 years) and male carriers (age, mean +/- SD: 37 +/- 6.7 years) did not differ significantly from age-matched normal females (35 +/- 5.4 years, n = 20) and normal males (35 +/- 6 years, n = 10), respectively. There were no significant differences in any of the ACTH-stimulated hormonal levels or ratios between the female carriers with a seriously deleterious genotype (n = 5) and the female carriers with mildly deleterious genotypes (n = 5). These hormonal levels and ratios in three genotype-normal females and one genotype-normal male overlapped with those of the carriers.
These data suggest that normal adrenal HSD3B2 activity is maintained in the genotype-proven carriers because heterodimers of mutant and wild-type HSD3B2 enzymes may be stable and exhibit similar activity compared to homodimers of wild-type enzymes, possibly by a relatively rate-unlimited effect of haplo-wild-type enzyme activity. However, we cannot preclude entirely the possibility of a limited expression of another HSD3B activity under ACTH stimulation contributing to the normal adrenal HSD3B activity in vivo in the HSD3B2 genotype-proven heterozygotes. Which mechanism plays a role in maintaining normal enzyme activity in the heterozygotes remains to be elucidated. The hormone findings in the genotypic-proven carriers for HSD3B2 deficiency also indicate that carriers for this disorder cannot be detected by a hormone test and can only be detected by HSD3B2 genotype study.
我们对3β-羟基类固醇脱氢酶（HSD3B2）活性相关的肾上腺类固醇生成功能以及3β-羟基类固醇脱氢酶2型（HSD3B2）基因已证实存在HSD3B2基因缺陷的先天性肾上腺皮质增生症（CAH）患者的临床正常家庭成员的HSD3B2基因型进行了研究，以确定经基因分型证实的HSD3B2缺陷携带者是否表现出酶活性降低，类似于CYP21基因突变携带者中肾上腺21-羟化酶活性的轻度降低。
设计/患者：对19名成年家庭成员（年龄中位数/范围：37/19 - 56岁）进行了研究，其中包括6名经基因分型证实存在HSD3B2缺陷的无关患者的13名女性和6名男性。
所有家庭成员均进行了HSD3B2 DNA分析和促肾上腺皮质激素（ACTH）刺激试验（静脉推注0.25 mg考的松龙），以测定肾上腺HSD3B活性。
13名女性中的10名和6名男性中的5名是HSD3B2基因一个等位基因中已证实或可预测有害突变的携带者，该突变在先证者中被发现。经基因分型证实的女性携带者（年龄，均值±标准差：36±6.7岁）和男性携带者（年龄，均值±标准差：37±6.7岁）中，ACTH刺激后的17-羟孕烯醇酮（δ5-17P）、17-羟孕酮（17-OHP）、皮质醇（F）、脱氢表雄酮（DHEA）和雄烯二酮（δ4-A）水平以及δ5-17P与17-OHP、δ5-17P与F以及DHEA与δ4-A的比值，以及δ5-17P和DHEA值的增量（ACTH刺激后 - 基线），与年龄匹配的正常女性（35±5.4岁，n = 20）和正常男性（35±6岁，n = 10）相比，差异均无统计学意义。具有严重有害基因型的女性携带者（n = 5）和具有轻度有害基因型的女性携带者（n = 5）之间，在任何ACTH刺激后的激素水平或比值上均无显著差异。3名基因正常的女性和1名基因正常的男性的这些激素水平和比值与携带者的水平重叠。
这些数据表明，经基因分型证实的携带者中肾上腺HSD3B2活性保持正常，因为突变型和野生型HSD3B2酶的异二聚体可能是稳定的，并且与野生型酶的同二聚体相比表现出相似的活性，这可能是由于单倍体野生型酶活性的相对速率不受限的作用。然而，我们不能完全排除在ACTH刺激下另一种HSD3B活性的有限表达有助于经基因分型证实的HSD3B2基因杂合子体内肾上腺HSD3B活性正常的可能性。哪种机制在维持杂合子的正常酶活性中起作用仍有待阐明。经基因分型证实的HSD3B2缺陷携带者的激素研究结果还表明，该疾病的携带者不能通过激素检测发现，只能通过HSD3B2基因分型研究来检测。
