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Identification and Functional Analysis of a New WNT4 Gene Mutation among 28 Adolescent Girls with Primary Amenorrhea and Müllerian Duct Abnormalities: A French Collaborative Study

Service d’Hormonologie (P.P., F.P., C.S.), Hôpital Lapeyronie, Centre Hospitalier Universitaire Montpellier, 34295 Montpellier cedex 5, France; Division of Paediatric Endocrinology and Diabetology (A.B.-L., D.K., E.S.), University Children’s Hospital, 8032 Zurich, Switzerland; Service de Gynécologie-Obstétrique (R.R.), Centre Hospitalier Intercommunal de Creteil, 94010 Creteil, France; Service d’Endocrinologie Pédiatrique (C.P.), Centre Hospitalier Universitaire de Toulouse, 31052 Toulouse, France; and Unité d’Endocrinologie et Gynécologie Pédiatrique (F.P., C.S.), Service de Pédiatrie I, Hôpital Arnaud de Villeneuve, Centre Hospitalier Universitaire Montpellier, 34090 Montpellier, France

Address all correspondence and requests for reprints to: Professor Charles Sultan, Service d’Hormonologie, Hôpital Lapeyronie, Centre Hospitalier Universitaire Montpellier, 34295 Montpellier cedex 5, France. E-mail: c-sultan{at}chu-montpellier.fr.

Context: Müllerian duct development depends on gene and hormone interactions. Female Wnt4-knockout mice lack müllerian ducts and are virilized due to the inappropriate expression of the enzymes required for androgen production (normally repressed in female ovary). The WNT4 mutation was recently reported to be associated with failure of müllerian duct formation and virilization in two 46, XX women.

Objectives: This collaborative work was designed to determine whether the WNT4 mutation could be identified in a group of adolescent girls with Mayer-Rokitansky-Küster-Hauser syndrome.

Results: We analyzed 28 DNA samples from adolescent girls with primary amenorrhea and failure of müllerian duct formation by direct sequencing and identified a new L12P mutation within exon 1 of the WNT4 gene. The substitution of leucine by proline is crucial for the conformation of the expressed protein. This amino acid substitution is unlikely to be a polymorphism because it was not found in 100 DNAs from control subjects. Functional analysis revealed that the mutation induces significantly increased expression of the enzymes involved in androgen biosynthesis (3β-hydroxysteroid dehydrogenase and 17-hydroxylase). It is interesting to note that the adolescent carrying the mutation was referred to our clinic for primary amenorrhea and hyperandrogenism (severe acne and plasma testosterone: 1.8 vs. 1.2 nmol/liter in controls). She also presented with uterine hypoplasia and follicle depletion.

Conclusions: We suggest that in adolescent girls with primary amenorrhea, müllerian duct abnormalities, and hyperandrogenism, a WNT4 mutation should be sought. Moreover, our data confirm that WNT4 is involved in the regulation of müllerian duct development and ovarian androgen biosynthesis. WNT4 may also contribute to human follicle development and/or maintenance.