Autosomal recessive segregation of a truncating mutation of anti-mulleriantype 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 TGF beta family whose members exert t heir effects by signaling through two related serine/threonine kinase recep tors. Mutations of the anti-Mullerian hormone type II receptor occur natura lly, causing the persistent Mullerian duct syndrome. In a family with two m embers with persistent Mullerian duct syndrome and one normal sibling, we d etected 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-bindi ng site of the kinase domain, is transmitted by the father to the two sons affected by persistent Mullerian duct syndrome, indicating a recessive auto somal transmission as in other cases of persistent Mullerian duct syndrome. Truncating mutations in receptors of the TGF beta family exert dominant ne gative activity, which was seen only when each of the mutant anti-Mullerian hormone receptors was overexpressed in an anti-Mullerian hormone-responsiv e cell line. We conclude that assessment of dominant activity in vitro, whi ch usually involves overexpression of mutant genes, does not necessarily pr oduce information applicable to clinical conditions, in which mutant and en dogenous genes are expressed on a one to one basis.