Mutations of the Anti-Muellerian Hormone Gene in Patients with Persistent Muellerian Duct Syndrome: Biosynthesis, Secretion, and Processing of the Abnormal Proteins and Analysis Using a Three-Dimensional Model

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2004-03, Vol.18 (3), p.708-721
• Main Authors: Belville, C, Van Vlijmen, H, Ehrenfels, C, Pepinsky, B, Rezaie, A R, Picard, J-Y, Josso, N, di Clemente, N, Cate, R L
• Format: Article
• Language: English
• ISSN: 0888-8809
• DOI: 10.1210/me.2003-0358

Anti-Muellerian hormone (AMH), a TGF- beta family member, determines whether an individual develops a uterus and Fallopian tubes. Mutations in the AMH gene lead to persistent Muellerian duct syndrome 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 persistent Muellerian duct syndrome 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, whereas 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, whereas 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.