Biason-Lauber A, De Filippo G, Konrad D, Scarano G, Nazzaro A, Schoenle E J
University Children's Hospital, Zurich, Switzerland.
Hum Reprod. 2007 Jan;22(1):224-9. doi: 10.1093/humrep/del360. Epub 2006 Sep 7.
The pathways leading to female sexual determination in mammals are incompletely defined. Loss-of-function mutations in the WNT4 gene appear to cause developmental abnormalities of sexual differentiation in women and mice. We recruited six patients with different degrees of Müllerian abnormalities, with or without renal aberrations and a normal female 46,XX karyotype. A clear androgen excess was found only in one patient. This 19-year-old woman was affected by primary amenorrhoea, absence of Müllerian ducts derivatives, clinical (acne and hirsutism) and biochemical (repeatedly high levels of testosterone) signs of androgen excess. Direct sequencing of her WNT4 gene followed by functional studies in human ovarian cells (OVCAR3) was performed. This patient carried the novel R83C loss-of-function dominant negative mutation in her WNT4, confirming the role of WNT4 in the development and maintenance of the female phenotype in women. Our study can also help refine the phenotype of WNT4 deficiency in humans. In fact, it appears that at least in this limited casuistic small group of patients, the absence of a uterus (and not other Müllerian abnormalities) and the androgen excess are the pathognomonic signs of WNT4 defects, suggesting that this might be a clinical entity distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome.
哺乳动物中导致雌性性别决定的途径尚未完全明确。WNT4基因的功能丧失突变似乎会导致女性和小鼠性分化的发育异常。我们招募了六名患有不同程度苗勒管异常的患者，这些患者有或没有肾脏畸形，且核型均为正常女性46,XX。仅在一名患者中发现明显的雄激素过多。这名19岁的女性患有原发性闭经，没有苗勒管衍生物，有临床（痤疮和多毛症）和生化（睾酮水平反复升高）雄激素过多的迹象。对她的WNT4基因进行了直接测序，随后在人卵巢细胞（OVCAR3）中进行了功能研究。该患者的WNT4基因携带新的R83C功能丧失显性负性突变，证实了WNT4在女性女性表型的发育和维持中的作用。我们的研究也有助于完善人类WNT4缺乏症的表型。事实上，至少在这一小批有限的病例中，子宫缺失（而非其他苗勒管异常）和雄激素过多似乎是WNT4缺陷的特征性体征，这表明这可能是一种与经典的 Mayer-Rokitansky-Kuster-Hauser 综合征不同的临床实体。
