Hauri-Hohl Annik, Meyer-Böni Monika, Lang-Muritano Mariarosaria, Hauri-Hohl Mathias, Schoenle Eugen J, Biason-Lauber Anna
Division of Endocrinology and Diabetology, University Children's Hospital ZürichDivision of Pediatrics, University Children's Hospital Zürich, Zürich, Switzerland.
Clin Endocrinol (Oxf). 2011 Jul;75(1):39-43. doi: 10.1111/j.1365-2265.2011.04012.x.
Aromatase deficiency in women is a rare 46, XX disorder of sex differentiation characterized by a defect in catalysing oestrogens from androgens.
To better understand this rare disorder, we searched for mutations in the CYP19A1 gene of an affected girl and analysed their functional consequences.
We examined a girl presenting with clitoral hypertrophy at birth and mild maternal virilization (acne) during pregnancy.
A genotype-phenotype correlation was found.
By direct sequencing of the CYP19A1 gene, we identified a heterozygous A>G mutation (c. A1374G) mutation in exon IX, leading to the missense p.N411S in the P450Aro protein and a heterozygous placenta promoter variant -41 base pairs upstream of exon I.1. Aromatase enzyme activity was completely lost when the mutant p.N411S protein was expressed in COS-1 cells. The placenta promoter variant had a significantly reduced (-50%) transactivation ability compared to wild-type.
Our data describe a novel loss-of-function missense mutation in CYP19A1 combined with the first-described variant of the placenta promoter with a significant reduction in function, likely to be the molecular basis of this rare 46, XX disorder of sex development. This seems to represent a unique case of aromatase deficiency occurring in utero only.
女性芳香化酶缺乏症是一种罕见的46，XX性分化障碍，其特征是在将雄激素催化为雌激素过程中存在缺陷。
为了更好地了解这种罕见疾病，我们在一名患病女孩的CYP19A1基因中寻找突变，并分析其功能后果。
我们检查了一名出生时出现阴蒂肥大且母亲在孕期有轻度男性化表现（痤疮）的女孩。
发现了基因型与表型的相关性。
通过对CYP19A1基因进行直接测序，我们在外显子IX中鉴定出一个杂合的A>G突变（c.A1374G），导致P450Aro蛋白中出现错义突变p.N411S，并且在外显子I.1上游41个碱基对处发现一个杂合的胎盘启动子变体。当突变的p.N411S蛋白在COS-1细胞中表达时，芳香化酶活性完全丧失。与野生型相比，胎盘启动子变体的反式激活能力显著降低（-50%）。
我们的数据描述了CYP19A1基因中一种新的功能丧失性错义突变，以及首次描述的胎盘启动子变体，其功能显著降低，这可能是这种罕见的46，XX性发育障碍的分子基础。这似乎代表了仅在子宫内发生的芳香化酶缺乏症的独特病例。
