Mutations of the AMH Type II Receptor in Two Extended Families with Persistent Müllerian Duct Syndrome: Lack of Phenotype/Genotype Correlation

Abstract

Our goal was to compare phenotype and genotype in two extended Middle-Eastern families affected by persistent Müllerian duct syndrome due to mutations of the type II anti-Müllerian hormone receptor (AMHR-II). The first, consanguineous, family consisted of 6 boys and 2 girls, the second consisted of 4 girls and 2 boys. In family I, 4 boys and 1 girl were homozygous for a stop mutation in the 9th exon of AMHR-II, removing part of the intracellular domain of the protein. In family II, 1 girl and 1 boy were homozygous for a transversion changing conserved histidine 254 into a glutamine. Both homozygous girls were normal. In the homozygous males, the degree of development of Müllerian derivatives was variable. The uterus was well developed in 2 boys of family I and in the patient from family II; however, in 1 subject from family I, Müllerian derivatives were undetectable. Taken together, the diversity of clinical symptoms within the same sibship and the lack of correlation between the development of the Müllerian derivatives and the severity of the molecular defects suggest highly variable penetrance of the abnormal alleles and/or the existence of other genetic or epigenetic modifiers of gene expression.

Constitutive negative regulation in the processing of the anti-Müllerian hormone receptor II

“…Accordingly, a similarly alternatively spliced AMHRII that is naturally expressed in rabbits does not bind ligand (di Clemente et al, 1994). In contrast to the constitutive cleavage of AMHRII, Alk5 (also known as TGFBR1; Liu et al, 2009;Mu et al, 2011), Alk3, Alk6 and BMPRII (Abdulhussein et al, 2008;Abduljabbar et al, 2012) were shown to undergo cleavage following phorbol ester stimulation, demonstrating that signaling by TGFb-SF receptors can also be dampened by inducible cleavage events.…”

The Persistent Müllerian Duct Syndrome: An Update Based Upon a Personal Experience of 157 Cases

“…The latter, a A>G change at the penultimate base of the intron 2, was found in 3 unrelated Brazilian patients and may represent a founder effect [Nishi et al, 2012]. Similarly, the 4 families affected by mutation c.301G>A, p.(Gly101Arg) all originate from the Middle East or Pakistan [Abduljabbar et al, 2012]. The 5 families affected by mutation c.500A>G, p.(Tyr167Cys) are Northern European.…”

“…2 ). The position of the testes/müllerian duct complex in PMDS may differ between brothers with the same genotype [Knebelmann et al, 1990;Abduljabbar et al, 2012;Nalbantoglu et al, 2015]. In patients described in the literature in whom molecular analysis has not been performed, the proportions are not very different: 41% for bilateral cryptorchidism, 32% for hernia uteri inguinalis , and 27% for transverse testicular ectopia.…”

“…Sometimes, müllerian derivatives are not found in subjects bearing an AMH or AMHRII mutation. They may be totally asymptomatic [Abduljabbar et al, 2012] or present with isolated transverse testicular ectopia.…”

Persistent Müllerian Duct Syndrome with Transverse Testicular Ectopia: A Novel Anti-Müllerian Hormone Receptor Mutation

“…AMHR2 gene mutations are located in the long arm 13.13 (12q.13.13) region of the 12 th chromosome. AMHR2 contains 11 exons and more than 27 mutations have already been described in this gene (14,15). The AMHR2 gene contains four intronic polymorphisms, located in t276a intron 1, c1280t intron 3, c1827t intron 5, and a6503g intron 10 (16).…”