Natural mutations of the anti-Müllerian hormone type II receptor found in persistent Müllerian duct syndrome affect ligand binding, signal transduction and cellular transport

Corinne Belville, Jean Didier Maréchal, Sophie Pennetier, Paul Carmillo, Laura Masgrau, Liza Messika-Zeitoun, Julie Galey, Gabrielle Machado, Dominique Treton, Jacques Gonzalès, Jean Yves Picard, Nathalie Josso, Richard L. Cate, Nathalie Di Clemente

Research output: Contribution to journalArticleResearchpeer-review

40 Citations (Scopus)

Abstract

The anti-Müllerian hormone type II (AMHRII) receptor is the primary receptor for anti-Müllerian hormone (AMH), a protein produced by Sertoli cells and responsible for the regression of the Müllerian duct in males. AMHRII is a membrane protein containing an N-terminal extracellular domain (ECD) that binds AMH, a transmembrane domain, and an intracellular domain with serine/threonine kinase activity. Mutations in the AMHRII gene lead to persistent Müllerian duct syndrome in human males. In this paper, we have investigated the effects of 10 AMHRII mutations, namely 4 mutations in the ECD and 6 in the intracellular domain. Molecular models of the extra- and intracellular domains are presented and provide insight into how the structure and function of eight of the mutant receptors, which are still expressed at the cell surface, are affected by their mutations. Interestingly, two soluble receptors truncated upstream of the transmembrane domain are not secreted, unless the transforming growth factor beta type II receptor signal sequence is substituted for the endogenous one. This shows that the AMHRII signal sequence is defective and suggests that AMHRII uses its transmembrane domain instead of its signal sequence to translocate to the endoplasmic reticulum, a characteristic of type III membrane proteins. © The Author 2009. Published by Oxford University Press. All rights reserved.
Original languageEnglish
Pages (from-to)3002-3013
JournalHuman Molecular Genetics
Volume18
Issue number16
DOIs
Publication statusPublished - 6 Aug 2009

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