Mutations of the anti-mullerian hormone gene in patients with persistent mullerian duct syndrome: biosynthesis, secretion, and processing of the abnormal proteins and analysis using a three-dimensional model.
Anti-Müllerian 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 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-beta-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.
Belville
Corinne
C
Unité de REcherches sur l'Endocrinologie du Développement (Institut National de la Santé et de la Recherche Médicale), Clamart, France.
Van Vlijmen
Herman
H
Ehrenfels
Christian
C
Pepinsky
Blake
B
Rezaie
Alireza R
AR
Picard
Jean-Yves
JY
Josso
Nathalie
N
di Clemente
Nathalie
N
Cate
Richard L
RL
D000595:Amino Acid Sequence; D000818:Animals; D054304:Anti-Mullerian Hormone; D019556:COS Cells; D006224:Cricetinae; D003545:Cysteine / Q000235:genetics; D012734:Disorders of Sex Development / Q000235:genetics*; D006023:Glycoproteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D013735:Testicular Hormones / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism*
D006023:Glycoproteins; D013735:Testicular Hormones; D054304:Anti-Mullerian Hormone; D003545:Cysteine