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Persistence of Müllerian derivatives in males
C Belville1, N Josso, J Y Picard
1Unité de Recherches sur l'Endocrinologie du Développement (INSERM), Ecole Normale Supérieure, Département de Biologie, 1 rue Maurice Arnoux, 92120 Montrouge, France. josso@wotan.ens.fr
Abstract:
The persistent müllerian duct syndrome is a rare, autosomal recessive disorder, characterized by the persistence of müllerian duct derivatives-uterus and fallopian tubes-in genetic males otherwise normally virilized. We have collected DNA from 69 families with this syndrome. In 45%, a mutation of the anti-müllerian hormone (AMH) gene was detected; 52% were homozygous. The level of circulating AMH was extremely low in the great majority of patients, even before puberty, when AMH levels are normally high. Single-strand conformation polymorphism (SSCP)-polymerase chain reaction (PCR) was a very effective screening method. In 39% of families, characterized by an AMH level normal for the age of the patient, a mutation of the type II receptor of AMH was detected by automatic sequencing, because SSCP-PCR was not very effective. Forty-eight percent of the mutations were homozygous. A 27-base-pair deletion in exon 10 was noted in 45% of the families. When this very common mutation is not taken into account, the proportion of recurrent mutations is 42% for the AMH gene and 33% for the AMH receptor type II gene. In 16% of families, no mutation of either the AMH or the AMH receptor gene was detectable; this group may correspond to mutations of unknown genes involved in AMH processing or in downstream AMH transduction.
Insights
Mutations in the anti-Müllerian hormone (AMH) gene or its receptor cause persistent Müllerian duct syndrome in genetic males. Genetic analysis identified specific mutations and highlighted potential unknown gene involvement.
Area of Science:
- Genetics
- Endocrinology
- Reproductive Biology
Background:
- Persistent Müllerian duct syndrome (PMDS) is a rare autosomal recessive disorder.
- It affects genetic males, leading to the presence of Müllerian duct derivatives (uterus, fallopian tubes) despite normal virilization.
Purpose of the Study:
- To identify the genetic basis of PMDS in affected families.
- To investigate the roles of the anti-Müllerian hormone (AMH) gene and its type II receptor in the syndrome's pathogenesis.
Main Methods:
- DNA analysis from 69 families with PMDS.
- Single-strand conformation polymorphism (SSCP)-polymerase chain reaction (PCR) for gene screening.
- Automatic sequencing for AMH receptor type II gene analysis.
- Measurement of circulating AMH levels.
Main Results:
- Mutations in the AMH gene were found in 45% of families, with 52% being homozygous.
- Mutations in the AMH type II receptor gene were identified in 39% of families, with 48% being homozygous.
- A recurrent 27-base-pair deletion in AMH exon 10 was observed in 45% of families.
- Low circulating AMH levels were noted in most patients.
- No mutations were found in 16% of families, suggesting other genetic factors.
Conclusions:
- Mutations in the AMH gene and its type II receptor are the primary causes of PMDS.
- Specific recurrent mutations, like the 27-bp deletion, are common.
- Further research is needed to identify genes involved in AMH processing or transduction in cases without identified AMH or AMH receptor mutations.