Categories: Reproductive system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 261550 (trait) , 600956 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2009

Cross-species summary: This is a type of XY difference of sexual development (XY DSD). The condition is characterized by the persistence of Müllerian derivatives (uterus and/or fallopian tubes) in otherwise normally virilized males (modified from [Orphanet:2856] caused by variants in the AMHR2 gene. See also OMIA:000791 Persistent Mullerian duct syndrome, generic

Species-specific name: Persistent Müllerian Duct Syndrome

Species-specific symbol: PMDS

Species-specific description: Information relating to persistent Mullerian duct syndrome due to variants in the AMRH2 gene were previously listed under OMIA:000791-9615 : Persistent Mullerian duct syndrome in Canis lupus familiaris. PMDS is a type of XY disorder of sexual development (XY DSD), characterized by the presence of Müllerian duct derivatives in otherwise normal males. The mode of inheritance for the PMDS trait in miniature schnauzers is sex-limited autosomal recessive. Affected dogs are 78,XY and have bilateral testes. Both affected and carrier males appear externally normal, although approximately 50% of affected dogs are unilaterally or bilaterally cryptorchid. Common sequelae are Sertoli cell tumors in cryptorchid PMDS males and pyometra. Treatment in affected dogs is gonadectomy and hysterectomy. Testing for the mutation prior to breeding is recommended, because affected dogs with scrotal testes are fertile and carriers have no clinical signs. Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT, updated by Imke Tammen [28/09/2023]

Inheritance: The mode of inheritance is sex-limited autosomal recessive, and both affected and carrier dogs are karyotypically normal [Wu et al., 2009]. Affected males are homozygous and will pass the mutation to all of their offspring. Carrier (heterozygous) males will pass the mutation to half their offspring, on average. Females are not affected, but can be either homozygous or heterozygous for the mutation. Homozygous carrier females will pass the mutation to all of their offspring and heterozygous carrier females will pass the mutation to half their offspring, on average.

Molecular basis: Wu et al. (2009) reported that the causative mutation of PMDS in the miniature schnauzer is a C to T transition in exon 3 of the Müllerian inhibiting substance type II receptor gene (MISRII, now known as AMHR2). Smit et al. (2018): "The genetic basis for PMDS in the Belgian Malinois was not determined, as no coding or splicing mutations were identified in either AMH or AMHR2 [in an affected dog]"

Clinical features: Homozygous affected males have normal male external genitalia, except that approximately 50% are unilaterally or bilaterally cryptorchid. PMDS males having at least one descended testicle can be fertile. Carrier males and carrier females are reproductively normal. PMDS dogs may present at any age as a dog with normal male external genitalia or a cryptorchid dog. If cryptorchid, they may present as an adult with signs of testicular tumor. As pyometra can be a sequelae, affected dogs may present with typical signs,such as polydipsia, polyuria and inappetance.

Pathology: During development of the male reproductive tract, Müllerian inhibiting substance (MIS), also known as Anti Mullerian hormone (AMh), causes regression of Mullerian duct precursors in males. MIS binding to its type II receptor (AMhR2) in the target organs is necessary to induce regression. If MIS signaling is faulty, the Müllerian ducts fail to regress in males, causing PMDS [Wu et al., 2009]. In addition to having male internal genitalia, PMDS males have bilateral oviducts, a complete uterus , a cervix, and the cranial part of the vagina, which ends in the dorsal prostate. There is a firm attachment between each cranial tip of the uterine horn and the caudal pole of the testis, which likely hinders testicular descent [Wu et al., 2009]. Some common complications are Sertoli cell tumors in cryptorchid PMDS dogs and pyometra. Pyometra may be facilitated by the narrow connection between the cranial vagina and the prostatic urethra, which allows pathogens to ascend to the uterus, but impedes purulent drainage [Wu et al., 2009]. On histologic section, cryptorchid testes from PMDS dogs lack germ cells, though scrotal testes appear normal.

Prevalence: Smit et al. (2018): "Genomic DNA from 216 Miniature Schnauzers (including one known PMDS case) was genotyped for the AMHR2 mutation", revealing "an AMHR2 mutation allele frequency of 0.16 and a carrier genotypic frequency of 0.27".

Control: To prevent PMDS, affected dogs should not be bred and carriers should not be bred to carriers. To reduce the frequency of the mutation in the miniature schnauzer breed, carriers should be removed from the breeding population. Because affected and carrier miniature schnauzers can have normal male external genitalia, testing for the mutation prior to breeding is recommended. As carrier females have no signs and are reproductively normal, testing for the mutation prior to breeding is recommended.

Genetic testing: The causative mutation of PMDS in the miniature schnauzer is a C to T transition in exon 3 of the Müllerian inhibiting substance type II receptor gene (AMHR2, Wu et al., 2009). A DNA test for this mutation can identify affected, carrier and normal miniature schnauzers (Pujar et al 2009). This is a PCR test followed by digestion of the PCR product by a restriction enzyme.

Breed: Miniature Schnauzer (Dog) (VBO_0200896).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: