Department of Pediatrics, University of California, San Francisco, San Francisco, California, 94143, USA.
J Clin Endocrinol Metab. 2013 Feb;98(2):713-20. doi: 10.1210/jc.2012-2828. Epub 2013 Jan 21.
The cholesterol side-chain cleavage enzyme P450scc, encoded by CYP11A1, converts cholesterol to pregnenolone to initiate steroidogenesis. P450scc deficiency can disrupt adrenal and gonadal steroidogenesis, resembling congenital lipoid adrenal hyperplasia clinically and hormonally; only 12 such patients have been reported previously.
We sought to expand clinical and genetic experience with P450scc deficiency.
We sequenced candidate genes in 7 children with adrenal insufficiency who lacked disordered sexual development. P450scc missense mutations were recreated in the F2 vector, which expresses the fusion protein P450scc-Ferredoxin Reductase-Ferredoxin. COS-1 cells were transfected, production of pregnenolone was assayed, and apparent kinetic parameters were calculated. Previously described P450scc mutants were assayed in parallel.
Four of five Bedouin children in one kindred were compound heterozygotes for mutations c.694C>T (Arg232Stop) and c.644T>C (Phe215Ser). Single-nucleotide polymorphism analysis confirmed segregation of these mutations. The fifth kindred member and another Bedouin patient presented in infancy and were homozygous for Arg232Stop. A patient from Fiji presenting in infancy was homozygous for c.358T>C (Arg120Stop). All mutations are novel. As assayed in the F2 fusion protein, P450scc Phe215Ser retained 2.5% of wild-type activity; previously described mutants Leu141Trp and Ala269Val had 2.6% and 12% of wild-type activity, respectively, and Val415Glu and c.835delA lacked detectable activity.
Although P450scc is required to produce placental progesterone required to maintain pregnancy, severe mutations in P450scc are compatible with term gestation; milder P450scc mutations may present later without disordered sexual development. Enlarged adrenals usually distinguish steroidogenic acute regulatory protein deficiency from P450scc deficiency, but only DNA sequencing is definitive.
胆固醇侧链裂解酶 P450scc，由 CYP11A1 编码，将胆固醇转化为孕烯醇酮以启动类固醇生成。P450scc 缺乏可破坏肾上腺和性腺类固醇生成，在临床上和激素上类似于先天性脂质性肾上腺增生；以前仅报道过 12 例此类患者。
我们试图扩大 P450scc 缺乏症的临床和遗传经验。
我们对 7 例无性发育障碍的肾上腺功能不全儿童进行候选基因测序。在 F2 载体中重新构建 P450scc 错义突变，该载体表达融合蛋白 P450scc-Ferredoxin Reductase-Ferredoxin。转染 COS-1 细胞，测定孕烯醇酮的产生，并计算表观动力学参数。同时测定了以前描述的 P450scc 突变体。
一个近亲中的 5 名贝都因儿童中的 4 名是突变 c.694C>T（Arg232Stop）和 c.644T>C（Phe215Ser）的复合杂合子。单核苷酸多态性分析证实了这些突变的分离。第五个家族成员和另一个贝都因患者在婴儿期表现为纯合子 Arg232Stop。一个来自斐济的婴儿期患者为 c.358T>C（Arg120Stop）纯合子。所有突变均为新突变。如 F2 融合蛋白中所测定的，P450scc Phe215Ser 保留了野生型活性的 2.5%；以前描述的突变体 Leu141Trp 和 Ala269Val 分别具有野生型活性的 2.6%和 12%，而 Val415Glu 和 c.835delA 则缺乏可检测的活性。
尽管 P450scc 是产生维持妊娠所需的胎盘孕酮所必需的，但 P450scc 的严重突变与足月妊娠相容；更温和的 P450scc 突变可能在没有性发育障碍的情况下较晚出现。增大的肾上腺通常可将类固醇急性调节蛋白缺乏症与 P450scc 缺乏症区分开来，但只有 DNA 测序才是明确的。
