OMIA:002775-9615 : Persistent Mullerian duct syndrome, AMHR2-related in Canis lupus familiaris (dog)
Categories: Reproductive system phene
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: 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]"
Have human generated variants been created, e.g. through genetic engineering and gene editing
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.
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|AMHR2||anti-Mullerian hormone receptor, type II||Canis lupus familiaris||27||NC_051831.1 (1796819..1791762)||AMHR2||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|280||Miniature Schnauzer||Persistent Mullerian duct syndrome||AMHR2||nonsense (stop-gain)||Naturally occurring variant||CanFam3.1||27||g.1794738G>A||c.262C>T||p.(R88*)||XM_543632.6; XP_543632.4; published as c.241C>T; coordinates in the table have been updated to a recent reference genome and / or transcript||2009||18723470|
Cite this entry
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2023||Meadows, J.R.S., Kidd, J.M., Wang, G.D., Parker, H.G., Schall, P.Z., Bianchi, M., Christmas, M.J., Bougiouri, K., Buckley, R.M., Hitte, C., Nguyen, A.K., Wang, C., Jagannathan, V., Niskanen, J.E., Frantz, L.A.F., Arumilli, M., Hundi, S., Lindblad-Toh, K., Ginja, C., Agustina, K.K., André, C., Boyko, A.R., Davis, B.W., Drögemüller, M., Feng, X.Y., Gkagkavouzis, K., Iliopoulos, G., Harris, A.C., Hytönen, M.K., Kalthoff, D.C., Liu, Y.H., Lymberakis, P., Poulakakis, N., Pires, A.E., Racimo, F., Ramos-Almodovar, F., Savolainen, P., Venetsani, S., Tammen, I., Triantafyllidis, A., vonHoldt, B., Wayne, R.K., Larson, G., Nicholas, F.W., Lohi, H., Leeb, T., Zhang, Y.P., Ostrander, E.A. :|
|Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture. Genome Biol 24:187, 2023. Pubmed reference: 37582787. DOI: 10.1186/s13059-023-03023-7.|
|2019||Nogueira, D.M., Armada, J.L.A., Penedo, D.M., Tannouz, V.G.S., Meyers-Wallen, V.N. :|
|Persistent Mullerian duct Syndrome in a Brazilian miniature schnauzer dog. An Acad Bras Cienc 91:e20180752, 2019. Pubmed reference: 31241703. DOI: 10.1590/0001-3765201920180752.|
|2018||Dzimira, S., Wydooghe, E., Van Soom, A., Van Brantegem, L., Nowacka-Woszuk, J., Szczerbal, I., Switonski, M. :|
|Sertoli cell tumour and uterine leiomyoma in Miniature Schnauzer dogs with persistent Müllerian duct syndrome caused by mutation in the AMHR2 gene. J Comp Pathol 161:20-24, 2018. Pubmed reference: 30173854. DOI: 10.1016/j.jcpa.2018.04.004.|
|Smit, M.M., Ekenstedt, K.J., Minor, K.M., Lim, C.K., Leegwater, P., Furrow, E. :|
|Prevalence of the AMHR2 mutation in Miniature Schnauzers and genetic investigation of a Belgian Malinois with persistent Müllerian duct syndrome. Reprod Domest Anim 53:371-376, 2018. Pubmed reference: 29194807. DOI: 10.1111/rda.13116.|
|2011||Breshears, M.A., Peters, J.L. :|
|Ambiguous genitalia in a fertile, unilaterally cryptorchid male miniature schnauzer dog. Vet Pathol 48:1038-40, 2011. Pubmed reference: 21248100. DOI: 10.1177/0300985810396104.|
|2010||Vegter, A.R., Kooistra, H.S., van Sluijs, F.J., van Bruggen, L.W., Ijzer, J., Zijlstra, C., Okkens, A.C. :|
|Persistent Mullerian duct syndrome in a Miniature Schnauzer dog with signs of feminization and a Sertoli cell tumour. Reprod Domest Anim 45:447-52, 2010. Pubmed reference: 18954385. DOI: 10.1111/j.1439-0531.2008.01223.x.|
|2009||Matsuu, A., Hashizume, T., Kanda, T., Nagano, M., Sugiyama, A., Okamoto, Y., Hikasa, Y. :|
|A case of persistent Müllerian duct syndrome with sertoli cell tumor and hydrometra in a dog J Vet Med Sci 71:379-81, 2009. Pubmed reference: 19346713.|
|Meyers-Wallen, VN. :|
|Review and update: genomic and molecular advances in sex determination and differentiation in small animals. Reprod Domest Anim 44 Suppl 2:40-6, 2009. Pubmed reference: 19754534. DOI: 10.1111/j.1439-0531.2009.01433.x.|
|Pujar, S., Meyers-Wallen, VN. :|
|A molecular diagnostic test for persistent Müllerian duct syndrome in miniature schnauzer dogs. Sex Dev 3:326-8, 2009. Pubmed reference: 20051676. DOI: 10.1159/000273264.|
|Wu, X., Wan, S., Pujar, S., Haskins, ME., Schlafer, DH., Lee, MM., Meyers-Wallen, VN. :|
|A single base pair mutation encoding a premature stop codon in the MIS type II receptor is responsible for canine persistent Mullerian duct syndrome. J Androl 30:46-56, 2009. Pubmed reference: 18723470. DOI: 10.2164/jandrol.108.005736.|
|1982||Marshall, LS., Oehlert, ML., Haskins, ME., Selden, JR., Patterson, DF. :|
|Persistent Mullerian duct syndrome in miniature schnauzers. J Am Vet Med Assoc 181:798-801, 1982. Pubmed reference: 7141975.|
|1976||Brown, T.T., Burek, J.D., McEntee, K. :|
|Male pseudohermaphroditism, cryptorchism, and Sertoli cell neoplasia in three miniature Schnauzers. J Am Vet Med Assoc 169:821-5, 1976. Pubmed reference: 10267.|
- Created by Imke Tammen2 on 28 Sep 2023
- Changed by Imke Tammen2 on 28 Sep 2023