Related Experiment Videos
Molecular genetics of the persistent müllerian duct syndrome: a study of 19 families
S Imbeaud1, D Carré-Eusèbe, R Rey
1Unité de Recherches sur l'Endocrinologie du Développement (INSERM) Ecole Normale Supérieure, Département de Biologie, Montrouge, France.
Abstract:
A rare form of familial male pseudohermaphroditism, the persistent Müllerian duct syndrome (PMDS) is characterized by persistence of uterus and Fallopian tubes in 46,XY phenotypic males and is ascribed to defects in the synthesis or action of anti-Müllerian hormone (AMH). Biologically, PMDS is heterogeneous: in some cases, bioactive AMH is normally expressed by testicular tissue while, in others, no AMH is produced, suggesting the possibility of an AMH gene mutation, several of which have already been described. Molecular analysis of the AMH gene has now been performed in 21 additional patients and their families. In 6 patients, with normal serum concentration of AMH, the AMH gene was normal or contained only polymorphisms and silent mutations, supporting the hypothesis that the condition is due to end-organ resistance. Nine novel mutations were discovered in the remaining subjects, with low or undetectable levels of serum AMH. These mutations, when present in homozygotes or compound heterozygotes, were associated with the PMDS phenotype, the same mutation never being observed in two different families. The three first exons of the AMH gene appear particularly mutation-prone, although they are less GC rich than the 2 last ones and code for the N-terminal part of the AMH protein, which is not in itself essential to bioactivity.
Insights
Persistent Müllerian duct syndrome (PMDS) in 46,XY males results from anti-Müllerian hormone (AMH) defects. Genetic analysis identified novel AMH gene mutations in some patients, while others showed end-organ resistance.
Area of Science:
- Genetics
- Endocrinology
- Developmental Biology
Background:
- Persistent Müllerian duct syndrome (PMDS) is a rare condition where 46,XY males retain female reproductive structures.
- This syndrome is linked to defects in anti-Müllerian hormone (AMH) synthesis or action.
Purpose of the Study:
- To investigate the genetic basis of PMDS in additional patients.
- To differentiate between AMH production defects and end-organ resistance.
Main Methods:
- Molecular analysis of the AMH gene in 21 patients and their families.
- Serum AMH concentration measurement.
- Genotyping for mutations, polymorphisms, and silent mutations.
Main Results:
- Six patients with normal AMH levels had normal AMH genes or only polymorphisms/silent mutations, suggesting end-organ resistance.
- Nine novel AMH gene mutations were found in patients with low/undetectable AMH, correlating with the PMDS phenotype.
- The first three exons of the AMH gene were identified as mutation-prone regions.
Conclusions:
- PMDS is genetically heterogeneous, caused by either AMH gene mutations or end-organ resistance.
- Novel mutations in the AMH gene are a significant cause of PMDS.
- Specific exons within the AMH gene are hotspots for mutations leading to PMDS.