AMH and AMH receptor defects in persistent Müllerian duct syndrome.

Anti-Müllerian hormone (AMH) produced by fetal Sertoli cells is responsible for regression of Müllerian ducts, the anlage for uterus and Fallopian tubes, during male sex differentiation. A member of the transforming growth factor-beta superfamily, AMH signals through two transmembrane receptors, type II which is specific and type I receptors, shared with the bone morphogenetic protein family. Mutations of the AMH and AMH receptor type II (AMHR-II) genes lead to persistence of the uterus and Fallopian tubes in males. Both conditions are transmitted according to a recessive autosomal pattern and are symptomatic only in males. Affected individuals are otherwise normally virilized, undergo normal male puberty; and may be fertile if testes, tightly attached to the Fallopian tubes, can be replaced in the scrotum. Approximately 85% of the cases are due, in similar proportions, to mutations of the AMH or AMHR-II gene. The genetic background does not influence the phenotype, the only difference is the level of circulating AMH which is normal for age in AMHR-II mutants and usually low or undetectable in AMH gene defects. This is due to lack of secretion, explained by the localization of the mutations in critical regions, based on the assumed 3D structure of the molecule. Similarly, lack of translocation to the surface membrane is responsible for the inactivity of AMHR-II molecules bearing mutations in the extracellular domain. In 15% of cases, the cause of the persistent Mullerian duct syndrome is unknown and could be related to complex malformations of the urogenital region, unrelated to AMH physiology.