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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

Unité de Recherches sur l’Endocrinologie du Développement (Institut National de la Santé et de la Recherche Médicale) (C.B., J.-Y.P., N.J., N.D.), 92140 Clamart, France; and Biogen, Inc. (H.V.V., C.E., B.P., A.R.R., R.L.C.), Cambridge, Massachusetts 02142

Address all correspondence and requests for reprints to: Dr. Richard L. Cate, Biogen, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142. E-mail: Richard.Cate{at}biogenidec.com.

Anti-Müllerian hormone (AMH), a TGF-ß family member, determines whether an individual develops a uterus and Fallopian tubes. Mutations in the AMH gene lead to persistent Müllerian 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-ß-like C-terminal dimer. We have studied the biosynthesis and secretion of wild-type AMH and of seven persistent Müllerian 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.

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