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This version published online on December 12, 2003
Molecular Endocrinology, doi:10.1210/me.2003-0358
A more recent version of this article appeared on March 1, 2004
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Submitted on September 15, 2003
Accepted on November 25, 2003

Mutations of the anti-Müllerian hormone gene in patients with persistent Müllerian duct syndrome: biosynthesis, secretion and processing of the abnormal proteins and analysis using a three-dimensional model

Corinne Belville1, Herman Van Vlijmen1, Christian Ehrenfels1, Blake Pepinsky1, Alireza R. Rezaie1, Jean-Yves Picard1, Nathalie Josso1, Nathalie di Clemente1, and Richard L. Cate1*

1 Unité de Recherches sur l'Endocrinologie du Développement (INSERM), 32 rue des Carnets, 92140 Clamart, France; Biogen, Inc., 14 Cambridge Center, Cambridge MA 02142, USA

* To whom correspondence should be addressed. E-mail: Rich_Cate{at}Biogen.com.

Anti-Müllerian hormone (AMH), a transforming growth factor-{beta} (TGF-{beta}) family member, determines whether an individual develops a uterus and Fallopian tubes. Mutations in the AMH gene lead to persistent Müllerian duct syndrome (PMDS) in males. The wild type human AMH protein is synthesized as a disulfide-linked dimer of two identical 70 kDa polypeptides, which undergoes proteolytic processing to generate a 110 kDa N-terminal dimer and a bioactive 25 kDa TGF-{beta}-like C-terminal dimer. We have studied the biosynthesis and secretion of wild type AMH and of seven PMDS proteins, containing mutations in either the N or C-terminal domain. Mutant proteins lacking the C-terminal domain are secreted more rapidly than full length AMH, while single amino acid changes in both domains can have profound effects on protein stability and folding. The addition of a cysteine in an N-terminal domain mutant, R194C, prevents proper folding, while the elimination of the cysteine involved in forming the interchain disulfide bond, in a C-terminal domain mutant, C525Y, leads to a truncation at the C-terminus. A molecular model of the AMH C-terminal domain provides insights into how some mutations could affect biosynthesis and function.




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