Lin D, Gitelman S E, Saenger P, Miller W L
Department of Pediatrics, University of California, San Francisco 94143.
J Clin Invest. 1991 Dec;88(6):1955-62. doi: 10.1172/JCI115520.
Congenital lipoid adrenal hyperplasia is the most severe form of congenital adrenal hyperplasia. Affected individuals can synthesize no steroid hormones, and hence are all phenotypic females with a severe salt-losing syndrome that is fatal if not treated in early infancy. All previous studies have suggested that the disorder is in the cholesterol side chain cleavage enzyme (P450scc), which converts cholesterol to pregnenolone. A newborn patient was diagnosed by the lack of significant concentrations of adrenal or gonadal steroids either before or after stimulation with corticotropin (ACTH) or gonadotropin (hCG). The P450scc gene in this patient and in a previously described patient were grossly intact, as evidenced by Southern blotting patterns. Enzymatic (polymerase chain reaction) amplification and sequencing of the coding regions of their P450scc genes showed these were identical to the previously cloned human P450scc cDNA and gene sequences. Undetected compound heterozygosity was ruled out in the new patient by sequencing P450scc cDNA enzymatically amplified from gonadal RNA. Northern blots of gonadal RNA from this patient contained normal sized mRNAs for P450scc and also for adrenodoxin reductase, adrenodoxin, sterol carrier protein 2, endozepine, and GRP-78 (the precursor to steroidogenesis activator peptide). These studies show that lipoid CAH is not caused by lesions in the P450scc gene, and suggest that another unidentified factor is required for the conversion of cholesterol to pregnenolone, and is disordered in congenital lipoid adrenal hyperplasia.
先天性类脂质肾上腺增生症是先天性肾上腺增生症最严重的一种形式。患病个体无法合成类固醇激素，因此均为表型女性，伴有严重的失盐综合征，若在婴儿早期不进行治疗则会致命。以往所有研究均表明，该病症是由胆固醇侧链裂解酶（P450scc）缺陷所致，该酶可将胆固醇转化为孕烯醇酮。一名新生儿患者在促肾上腺皮质激素（ACTH）或促性腺激素（hCG）刺激前后，肾上腺或性腺类固醇的浓度均未显著升高，据此被诊断为此病。通过Southern印迹图谱证实，该患者以及之前描述的一名患者的P450scc基因大体完整。对其P450scc基因编码区进行酶促（聚合酶链反应）扩增和测序，结果显示这些区域与先前克隆的人P450scc cDNA及基因序列相同。通过对从性腺RNA酶促扩增得到的P450scc cDNA进行测序，排除了新患者中未检测到的复合杂合性。该患者性腺RNA的Northern印迹显示，P450scc以及肾上腺皮质铁氧化还原蛋白还原酶、肾上腺皮质铁氧化还原蛋白、固醇载体蛋白2、内啡肽和GRP-78（类固醇生成激活肽前体）的mRNA大小正常。这些研究表明，类脂质先天性肾上腺增生症并非由P450scc基因的病变引起，提示胆固醇转化为孕烯醇酮需要另一种未明确的因子，而该因子在先天性类脂质肾上腺增生症中出现紊乱。
