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

Abstract

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.

Functional and Molecular Characterization of Naturally Occurring Mutations in the Oocyte-secreted Factors Bone Morphogenetic Protein-15 and Growth and Differentiation Factor-9

“…There have been reports of mutations in other TGF-␤ superfamily members that appear to have primary effects on the intracellular processing and secretion of the mature proteins (23)(24)(25). The effects of these mutations bear resemblance to the substitution mutations in BMP-15 reported here; however, our findings in BMP-15 are unique in that we cannot detect any defects in the processing, secretion, dimerization, or biological activity of BMP-15 caused by the FecX mutations unless the mutant BMP-15 is co-expressed with GDF-9.…”

Anti-Müllerian hormone in disorders of sex determination and differentiation

“…The AMH-negative variant is due to mutations in the AMH gene, resulting in complete lack of AMH production or secretion. These patients have very low or undetectable serum AMH concentrations because (56), in rare cases with AMH mutations, serum AMH concentration may be normal for age; these mutations impair bioactivity but not secretion (57). The AMH-positive variant is generally due to mutations in the gene coding for AMH receptor type II (AMHR-II); as expected, these patients have a normal AMH serum concentration for their age (58) (figure 5).…”

Persistent Müllerian duct syndrome: A novel mutation in the Αnti-Müllerian Ηormone gene

“…AMHR2 gene mutations (PMDS type II) are responsible for the remaining 40% of cases. 3,4 Patients with AMH or AMHR2 gene mutations show no differences in the anatomical phenotype. However, patients with AMH gene defects have low or undetectable AMH levels, whereas those with AMHR mutations have normal or elevated levels of AMH.…”

“…Although autosomal recessive, autosomal dominant, and X-linked inheritance patterns have been reported in PMDS, most of the reported cases were isolated. [2][3][4] The AMH gene was mapped by Cohen-Hauguenaure in 1987. 5 Since then, more than 200 PMDS cases have been reported in the literature.…”

“…5 Since then, more than 200 PMDS cases have been reported in the literature. [1][2][3][4]6 In this case report, we describe the clinical features of a case of PMDS type I with a novel AMH mutation.…”