title: Autosomal recessive segregation of a truncating mutation of anti-Müllerian type II receptor in a family affected by the persistent Müllerian duct syndrome contrasts with its dominant negative activity in vitro.
abstract: Anti-Müllerian hormone belongs to the TGFbeta family whose members exert their effects by signaling through two related serine/threonine kinase receptors. Mutations of the anti-Müllerian hormone type II receptor occur naturally, causing the persistent Müllerian duct syndrome. In a family with two members with persistent Müllerian duct syndrome and one normal sibling, we detected two novel mutations of the anti-Müllerian 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 Müllerian duct syndrome, indicating a recessive autosomal transmission as in other cases of persistent Müllerian duct syndrome. Truncating mutations in receptors of the TGFbeta family exert dominant negative activity, which was seen only when each of the mutant anti-Müllerian hormone receptors was overexpressed in an anti-Müllerian 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.
authors.affiliation: Unité de Recherches sur l'Endocrinologie du Développement, INSERM, U-493, Département de Biologie, Ecole Normale Supérieure, 92120 Montrouge, France.
authors.forename: L
authors.initials: L
authors.lastname: Messika-Zeitoun
authors.forename: L
authors.initials: L
authors.lastname: Gouédard
authors.forename: C
authors.initials: C
authors.lastname: Belville
authors.forename: M
authors.initials: M
authors.lastname: Dutertre
authors.forename: L
authors.initials: L
authors.lastname: Lins
authors.forename: S
authors.initials: S
authors.lastname: Imbeaud
authors.forename: I A
authors.initials: IA
authors.lastname: Hughes
authors.forename: J Y
authors.initials: JY
authors.lastname: Picard
authors.forename: N
authors.initials: N
authors.lastname: Josso
authors.forename: N
authors.initials: N
authors.lastname: di Clemente
mesh_terms: D000818:Animals; D054304:Anti-Mullerian Hormone; D001710:Biotin; D015152:Blotting, Northern; D019556:COS Cells; D002648:Child; D003001:Cloning, Molecular; D015536:Down-Regulation / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D006023:Glycoproteins; D006131:Growth Inhibitors / Q000235:genetics*; D006801:Humans; D008297:Male; D009095:Mullerian Ducts / Q000502:physiology*; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D011956:Receptors, Cell Surface / Q000235:genetics; D018000:Receptors, Peptide / Q000235:genetics*; D018125:Receptors, Transforming Growth Factor beta; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D013735:Testicular Hormones / Q000235:genetics*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
chemical_list: D006023:Glycoproteins; D006131:Growth Inhibitors; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D013735:Testicular Hormones; D016212:Transforming Growth Factor beta; C084621:anti-Mullerian hormone receptor; D001710:Biotin; D054304:Anti-Mullerian Hormone