Autosomal recessive segregation of a truncating mutation of anti-Mullerian type II receptor in a family affected by the persistent Mullerian duct syndrome contrasts with its dominant negative activity in vitro.

Anti-Mullerian hormone belongs to the TGFbeta family whose members exert their effects by signaling through two related serine/threonine kinase receptors. Mutations of the anti-Mullerian hormone type II receptor occur naturally, causing the persistent Mullerian duct syndrome. In a family with two members with persistent Mullerian duct syndrome and one normal sibling, we detected two novel mutations of the anti-Mullerian hormone type II receptor gene. One, transmitted by the mother to her three sons, is a deletion of a single base leading to a stop codon, causing receptor truncation after the transmembrane domain. The other, a missense mutation in the substrate-binding site of the kinase domain, is transmitted by the father to the two sons affected by persistent Mullerian duct syndrome, indicating a recessive autosomal transmission as in other cases of persistent Mullerian duct syndrome. Truncating mutations in receptors of the TGFbeta family exert dominant negative activity, which was seen only when each of the mutant anti-Mullerian hormone receptors was overexpressed in an anti-Mullerian hormone-responsive cell line. We conclude that assessment of dominant activity in vitro, which usually involves overexpression of mutant genes, does not necessarily produce information applicable to clinical conditions, in which mutant and endogenous genes are expressed on a one to one basis.