Zhu Wen-Jiao, Cheng Tong, Zhu Hui, Han Bing, Fan Meng-Xia, Gu Ting, Zhao Shuang-Xia, Liu Yang, Cheng Kai-Xiang, Song Huai-Dong, Qiao Jie
Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 369 Zhizaoju Road, Shanghai 200011, China.
Central Laboratory, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Mol Cell Endocrinol. 2016 Sep 15;433:66-74. doi: 10.1016/j.mce.2016.05.025. Epub 2016 May 30.
Aromatase deficiency is a rare autosomal recessive disorder that is caused by an impairment of androgen conversion to estrogens. Affected 46, XX individuals generally present with virilization of external genitalia at birth and mutations in CYP19A1 gene.
This study described the clinical features and molecular basis of a Chinese 46, XX girl born with ambiguous genitalia and investigated the functional alteration of two novel mutations of the CYP19A1 gene.
Obvious prepartum virilization and remarkably elevated testosterone were observed in the mother, who was initially suspected to have a testosterone-producing ovarian tumor. Clinical phenotypes and hormone profiles of the patient and her mother were investigated. Genotyping analyses of the CYP19A1 gene were performed in the patient and her parents. Functional impairment of the mutations was explored using three-dimensional computer model and mutagenesises in vitro transfection assays. A compound heterozygous mutation of the CYP19A1 gene was revealed in the patient, with a G deletion in nucleotide 264 of exon 3 in one allele and a 23-bp insertion in exon 9 in another allele; both mutations resulted in reading frame-shifts that led to truncated proteins of 87 and 360 amino acids, respectively. Molecular modeling analysis suggested that the two renascent truncated proteins lacked crucial amino acids that were involved in substrate access and catalysis as well as heme-binding region. Functional studies in transfected HEK-293T cells exhibited a nearly complete abolishment of enzyme activity, which may underlie the phenotype and hormone profile.
Two novel CYP19A1 mutations were identified in a Chinese girl born with ambiguous genitalia and severe maternal virilization during pregnancy. Maternal virilization should prompt consideration of aromatase deficiency, preventing unnecessary interventions in pregnancy. This study broadens the spectrum of phenotype and genetic mutations of this rare disorder.
芳香化酶缺乏症是一种罕见的常染色体隐性疾病，由雄激素向雌激素转化受损引起。受影响的46, XX个体通常在出生时表现为外生殖器男性化以及CYP19A1基因突变。
本研究描述了一名出生时生殖器模糊的中国46, XX女孩的临床特征和分子基础，并研究了CYP19A1基因两个新突变的功能改变。
在母亲身上观察到明显的产前男性化和睾酮显著升高，最初怀疑她患有产生睾酮的卵巢肿瘤。对患者及其母亲的临床表型和激素谱进行了研究。对患者及其父母进行了CYP19A1基因的基因分型分析。使用三维计算机模型和体外转染试验中的诱变来探索突变的功能损害。在患者中发现了CYP19A1基因的复合杂合突变，一个等位基因中外显子3的核苷酸264处有一个G缺失，另一个等位基因中外显子9中有一个23 bp的插入；这两个突变均导致读码框移位，分别产生87和360个氨基酸的截短蛋白。分子建模分析表明，这两个新生的截短蛋白缺乏参与底物进入、催化以及血红素结合区域的关键氨基酸。在转染的HEK-293T细胞中的功能研究显示酶活性几乎完全丧失，这可能是表型和激素谱的基础。
在一名出生时生殖器模糊且母亲孕期严重男性化的中国女孩中鉴定出两个新的CYP19A1突变。母亲的男性化应促使考虑芳香化酶缺乏症，避免孕期进行不必要的干预。本研究拓宽了这种罕见疾病的表型和基因突变谱。
