Human Molecular Genetics Advance Access originally published online on May 20, 2009
Human Molecular Genetics 2009 18(16):3002-3013; doi:10.1093/hmg/ddp238
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Natural mutations of the anti-Müllerian hormone type II receptor found in persistent Müllerian duct syndrome affect ligand binding, signal transduction and cellular transport
1 INSERM U782, 32 rue des Carnets, Clamart F-92140, France 2 Univ Paris-Sud, UMR-S0782, Clamart F-92140, France 3 Unitat de Química Física, Departament de Química, Universitat Autònoma de Barcelona, Edifici C.n. 08193, Cerdanyola, Barcelona, Spain 4 Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA 5 Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola, Barcelona, Spain
* To whom correspondence should be addressed. Tel: +33 141288029; Fax: +33 141288028; Email: nathalie.diclemente{at}u-psud.fr
Received April 8, 2009; Accepted May 16, 2009
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 authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.