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

Context: Mullerian duct development depends on gene and hormone interactions. Female Wnt4-knockout mice lack mullerian 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 mullerian 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-Kuster-Hauser syndrome. Results: We analyzed 28 DNA samples from adolescent girls with primary amenorrhea and failure of mullerian 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. Funct...