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Baker Institute |  Faculty



Vicki Meyers-Wallen, VMD, PhD, Diplomate ACT — Inherited Disorders of the Reproductive Tract
Associate Professor of Genetics and Reproduction

1. Persistent Mullerian Duct Syndrome (PMDS)

DNA TEST FOR THE MINIATURE SCHNAUZER – information for breeders

Several cases of PMDS in Miniature Schnauzers have been reported in the USA and Europe over the past 20 years. We have developed a DNA test for Persistent Mullerian Duct Syndrome (PMDS) in the Miniature Schnauzer. In addition to determining which dogs are affected or carriers, this test can also determine which males and females are free of the mutation, and thus are clear for breeding. Routine testing would reduce the frequency of this mutation, allowing PMDS to be eliminated from the Miniature Schnauzer breed. Our laboratory previously determined that PMDS in this breed is inherited as a sex-limited autosomal recessive trait and we recently reported the causative mutation (Journal of Andrology 2009). The article is freely available through Pub Med Central (see sidebar, Publications).

Health problems due to PMDS
The problem is that a uterus develops in male Miniature Schnauzers that carry two copies of the PMDS mutation. (Yes, a male with a uterus!) Because approximately 50% of PMDS males look normal externally, they are not identified by experienced breeders or through regular physical examination by veterinarians. Such dogs are fertile and all of their offspring are obligate carriers. These dogs are rarely diagnosed as having PMDS until health problems arise. Only after the diagnosis of PMDS is made is it clear that both of his parents are carriers. By then the affected dog and his parents have usually produced more offspring.
     The other 50% of PMDS males also look like males externally but additionally have cryptorchidism (failure of one or both testes to descend into the scrotum). The uterus is sometimes identified when these cryptorchid PMDS males are neutered. If they are not neutered, tumors often develop in the undescended testes.
     The major life threatening health problem for all PMDS males is development of uterine infection (pyometra), which can arise in young or old dogs. Delay in diagnosis of pyometra and PMDS is common, as neither the owner, breeder or veterinarian is expecting a uterine infection in a male dog. Repeated urinary tract infections can also occur. All PMDS dogs and carriers can be diagnosed by DNA testing as pups and prior to developing pyometra, urinary tract infections or testicular tumors.

Which dogs should be tested?
The DNA test can identify all Miniature Schnauzers that carry this PMDS mutation, including carrier males and females, as well as affected males. Females can carry one or two copies of the mutation with no health consequences, but can pass the mutation to their offspring. Male carriers have one copy of the mutation and are fertile. PMDS males have two copies of the mutation, thus all of their offspring will receive the mutation. Certainly any dog that is related to a known PMDS male should be tested: siblings, grandparents, aunts, uncles, and so forth. Testing the parents will determine whether they carry one or two copies of the mutation. Such testing will also allow the breeder to identify which dogs are clear of the mutation, allowing the line to be further perpetuated from them.
     Remember that it is difficult to identify PMDS dogs without DNA testing. Therefore, even if PMDS has not yet been identified in a particular line, it is prudent to test at least the foundation males and females to be certain that the line is clear. Subsequently, any dog that is not known to be PMDS clear should be tested before it is bred into a clear line.
     Contact Dr. Vicki Meyers-Wallen if you want to test your dogs or if think you have an affected dog. We can assist you and your veterinarian with diagnosis, genetic testing and genetic counseling. The contact information is: E-mail: vnm1@cornell.edu, telephone: 607 256 5683. All information will be kept in strictest confidence.

Persistent Mullerian Duct Syndrome (PMDS)- information for clinicians/researchers

Persistent Mullerian Duct Syndrome has been reported in Miniature Schnauzers in the USA and Europe and in Basset Hounds in Europe. In collaboration with others, our laboratory identified the causative mutation in the Miniature Schnauzer (Wu et al. 2009. J Androl, Pub Med PMID in process, see sidebar, Publications). Affected Miniature Schnauzers are XY males with bilateral testes, oviducts, uterus and cranial vagina in addition to epididymides, vasa deferentia, and the prostate gland. No abnormalities have been detected in homozygous or heterozygous females. PMDS in Miniature Schnauzers is inherited as a sex-limited autosomal recessive trait.

Diagram of normal male organs (A) and organs found in PMDS affected dogs (B).

Diagram of normal male organs (A) and organs found in PMDS affected dogs (B).

Cross section of the uterine horn (arrow) and vas deferens (arrowhead) from a PMDS affected dog.

Cross section of the uterine horn (arrow) and vas deferens (arrowhead) from a PMDS affected dog.

Approximately 50% of PMDS Miniature Schnauzers have unilateral or bilateral cryptorchidism. The undescended testes do not produce sperm, and can develop tumors. However 50% of PMDS Miniature Schnauzers have NORMAL testis descent and thus veterinarians may not suspect PMDS. These dogs are not diagnosed by routine physical examination, are fertile, and their offspring are obligate carriers of the mutation.

High power microscopic view of seminiferous tubules in testes from a PMDS affected dog. A. The cryptorchid testis has only Sertoli cells (arrow) and no sperm producing cells in the tubules. B. The descended testis has Sertoli cells and developing sperm cells in the tubule.

High power microscopic view of seminiferous tubules in testes from a PMDS affected dog. A. The cryptorchid testis has only Sertoli cells (arrow) and no sperm producing cells in the tubules. B. The descended testis has Sertoli cells and developing sperm cells in the tubule.

 

Health problems

Infected uterus (pyometra) removed from a PMDS affected dog. Arrow indicates one uterine horn that is very dilated by fluid accumulation. Testes (cut in half) are indicated by arrowheads. The larger testis contains a tumor.

Infected uterus (pyometra) removed from a PMDS affected dog. Arrow indicates one uterine horn that is very dilated by fluid accumulation. Testes (cut in half) are indicated by arrowheads. The larger testis contains a tumor.

All PMDS males are subject to associated health problems of urinary tract infections and/or pyometra, which are potentially fatal. The veterinarian is unlikely to suspect pyometra in a dog that looks like a male, and this can cause delay in diagnosis. Signs of polydipsia, polyuria, fever, hematuria or pyuria in male Miniature Schnauzers should prompt further diagnostic procedures such as ultrasonography and contrast radiography. The uterus and vagina may be misdiagnosed as large prostatic cysts through such procedures, but surgical exploration and histopathology will confirm PMDS. Since PMDS dogs should be prevented from producing offspring, surgical treatment for PMDS should include hysterectomy and castration. Note that the proximal uterine horns are attached to the testes and the vagina terminates in the dorsal prostate. If the vagina is distended and infected, it may require marsupialization, using methods similar to those employed for prostatic cysts.

 

Molecular pathogenesis

Low power microscopic view of a testis from a PMDS affected canine embryo. Arrow indicates seminiferous tubule staining positive for MIS protein.

Low power microscopic view of a testis from a PMDS affected canine embryo. Arrow indicates seminiferous tubule staining positive for MIS protein.

In normal male development, the structure that can develop into the uterus (Mullerian or Paramesonephric ducts) disintegrates under the influence of a hormone secreted by the embryonic testis. This hormone is called Mullerian Inhibiting Substance (MIS) or Anti-Mullerian hormone (AMh). Our studies showed that MIS mRNA and protein are produced by the testes of PMDS affected embryos during the entire embryonic critical period for Mullerian duct regression (Day 34-36 of a 65 day gestation).

Using bioassays we showed that the MIS produced by PMDS dogs is biologically active. Therefore we suspected that the cause of PMDS in the Miniature Schnauzer was a defect in the MIS receptor. Subsequently, in collaboration with others we identified the causative mutation as a single base pair substitution in MISRII that introduces a stop codon in exon 3. This results in an mRNA transcript that is 243 rather than 1806 nucleotides. The homozygous mutation terminates translation at 80 amino acids, eliminating much of the extracellular domain and the entire transmembrane and intracellular signaling domains of the receptor. Therefore it is likely that the MIS type II receptor is completely dysfunctional in PMDS Miniature Schnauzers.

2. SRY-negative XX sex reversal (XXSR)

SRY-negative XX sex reversal is an inherited disorder that causes infertility and sterility in some breeds of purebred dogs. At present, this inherited disorder is well documented in the following breeds in the USA:

American and English cocker spaniels
Beagle
Chinese pug
German shorthaired pointer
Kerry blue terrier
Norwegian elkhound
Soft-coated wheaten terrier
Weimaraner

Breeds in which SRY-negative XXSR has been diagnosed by our laboratory or by others in the USA or Europe (updated 2009) include:

Afghan hound
American pit bull terrier
American Staffordshire terrier
Australian shepherd
Basset hound
Border Collie
Brussels Griffon
Cavalier King Charles spaniel
Doberman pinscher
French bull dog
German pinscher
Golden Retriever
Jack Russell Terrier
Labrador Retriever
Miniature pinscher
Tibetan terrier
Vizsla
Walker Hound
West highland white terrier

Affected dogs have female chromosomes (XX), although dogs with male sex chromosomes (XY) can be carriers of XXSR. Normal dogs with female sex chromosomes develop only ovaries. Dogs affected with XXSR usually develop both ovarian and testis tissue (ovotestes). On rare occasions, affected dogs develop only testis tissue. As a result, the rest of the reproductive tract develops abnormally. This leads to infertility and sterility.

Externally - Affected dogs can have any of the following signs:

A vulva that is shaped like a prepuce.

A. Normal vulva in a female pup. B. Prepuce-like genitals in an XXSR affected littermate to (A).

A. Normal vulva in a female pup. B. Prepuce-like genitals in an XXSR affected littermate to (A).

An enlarged clitoris (containing a bone) that may protrude from the vulva.

Dog affected with XXSR showing enlarged clitoris containing a bone (arrow). This structure often protrudes from the vulva in affected dogs.

Dog affected with XXSR showing enlarged clitoris containing a bone (arrow). This structure often protrudes from the vulva in affected dogs.

A longer distance between the anus and the vulva than is normally seen in females (the vulva may be located very near the belly) or a small prepuce.

A. Normal pup on the left showing position of umbilicus (arrowhead) and prepuce (arrow). The littermate on the right is affected with XXSR. Note the difference in position of the small prepuce (arrow) in relationship to the umbilicus (arrowhead) as compared to the normal male on the left. B. Affected pup from (A) at approximately 10 months of age. Note abnormal conformation of the prepuce/vulva (arrow).

A. Normal pup on the left showing position of umbilicus (arrowhead) and prepuce (arrow). The littermate on the right is affected with XXSR. Note the difference in position of the small prepuce (arrow) in relationship to the umbilicus (arrowhead) as compared to the normal male on the left. B. Affected pup from (A) at approximately 10 months of age. Note abnormal conformation of the prepuce/vulva (arrow).

If they have a penis-like structure they have hypospadias (the urethra does not open at the tip but opens farther caudally).

Close up of a penis-like structure of a dog affected with XXSR showing hypospadias. A catheter has been placed in the urethra. The urethral orifice (arrow) is located farther caudally than the normal position (indicated by arrowhead).

Close up of a penis-like structure of a dog affected with XXSR showing hypospadias. A catheter has been placed in the urethra. The urethral orifice (arrow) is located farther caudally than the normal position (indicated by arrowhead).

Internally - Affected dogs usually have:

  • Bilateral ovotestes or testes
  • One ovotestis and one ovary
Microscopic views of gonads from dogs affected with XXSR A. Ovotestis. Arrow indicates testis tissue in the center of the ovotestis. Arrowhead indicates ovarian tissue with follicles developing on the external surface of the ovotestis. B. Ovotestis at higher power magnification showing ovarian tissue at the surface (arrowhead) and testis tissue internally (arrow). C. Higher power magnification of the testis portion of the ovotestis. Seminiferous tubules contain only Sertoli cells (arrow) and contain no sperm producing cells.

Microscopic views of gonads from dogs affected with XXSR A. Ovotestis. Arrow indicates testis tissue in the center of the ovotestis. Arrowhead indicates ovarian tissue with follicles developing on the external surface of the ovotestis. B. Ovotestis at higher power magnification showing ovarian tissue at the surface (arrowhead) and testis tissue internally (arrow). C. Higher power magnification of the testis portion of the ovotestis. Seminiferous tubules contain only Sertoli cells (arrow) and contain no sperm producing cells.

Most often, affected dogs cannot be differentiated from normal females during a spay/neuter operation even if the veterinarian is an expert in XXSR because testicular tissue is often in the center of the gonad. Carriers look like normal females or normal males. Correct diagnosis depends upon microscopic examination of the gonads by a pathologist who is familiar with XXSR. When this is done, either one ovary and an ovotestis, two ovotestes, or two testes are usually found.

Uterus and gonads of a dog affected with XXSR. Double arrows indicate the uterine horns. Single arrow indicates an epididymis adjacent to an ovotestis.

Uterus and gonads of a dog affected with XXSR. Double arrows indicate the uterine horns. Single arrow indicates an epididymis adjacent to an ovotestis.

When only testes are found, they are usually in the abdomen. All affected dogs have a complete uterus. Many have an epididymis adjacent to the ovotestis or testis.

Also, all affected dogs have female sex chromosomes (XX), as determined by chromosome analysis (karyotype) and no Y chromosome.

At present, correct diagnosis of affected dogs is difficult, and there is no practical method to identify carriers.

PCR Tests Polymerase Chain Reaction (PCR) tests for the presence of canine Sry in DNA from normal and affected dogs. The Sry gene is normally located only on the Y chromosome. Normal female (F) and affected (A) dogs do not have Sry in their DNA. Normal males (M) have Sry. Both normal and affected dogs have the control product from the HPRT gene, which is on the X chromosome.

PCR Tests Polymerase Chain Reaction (PCR) tests for the presence of canine Sry in DNA from normal and affected dogs. The Sry gene is normally located only on the Y chromosome. Normal female (F) and affected (A) dogs do not have Sry in their DNA. Normal males (M) have Sry. Both normal and affected dogs have the control product from the HPRT gene, which is on the X chromosome.

We hope to increase breeders' awareness of XXSR by describing the common findings in affected dogs. We need to know if this problem has been recognized in your breeds and how many dogs have been affected.

We are working to identify the gene that causes this problem so that we can develop a DNA test. A DNA test will allow us to clearly identify both carrier and affected dogs, providing a practical method to improve breeding performance in these breeds.

You can help by contacting Dr. Vicki Meyers-Wallen if you think you have an affected dog. All information will be kept in the strictest confidence. If you wish, we can assist you and your veterinarian in diagnosis and genetic counseling.

 

PMDS:

Persistent Mullerian Duct Syndrome (PMDS) occurs in Miniature Schnauzers in the USA and the Basset hound in Europe. We have identified affected Miniature Schnauzers are XY males with bilateral testes, oviducts, uterus and cranial vagina.

Approximately half the affected Miniature Schnauzers have one or two undescended testes (unilateral or bilateral cryptorchidism). Undescended testes do not produce sperm, and can develop tumors. However, half the affected Miniature Schnauzers have normal testis decent. These primarily are undetectible by physical examination and can produce offspring, all of which will carry the mutation. Affected dogs can develop uterine infections (pyometra), which is a potentially fatal disease.

The veterinarian is unlikely to suspect pyometra in a dog that looks like a male, and this can cause delay in diagnosis.

In normal male development, the tissue that can develop into the uterus (Mullerian or Paramesonephric ducts) disintegrates under the influence of a hormone secreted by the embryonic testis. This hormone is called Mullerian Inhibiting Substance (MIS), or Anti-Mullerian hormone (AMh). Our studies showed that MIS mRNA and protein are produced by the testes of PMDS affected embryos during the entire embryonic critical period for Mullerian duct regression (day 34-46 gestation).

We also used bioassays to show that the MIS produced by PMDS dogs is biologically active MIS. Therefore, we suspected a MIS receptor defect. Our studies identified a mutation in the MIS receptor in the Miniature Schnauzer. 

3. Cryptorchidism

Identification and health consequences
Cryptorchidism is the failure of one or both testes to descend into the scrotum. It can occur as the only defect in male development (isolated cryptorchidism) or in association with other disorders of sexual development, such as PMDS or SRY-negative XXSR (above). In the dog, both testes normally descend into the scrotum by 2 weeks after birth (even though one can not easily feel them there at that time), but should certainly be detectable in the scrotum by 6 weeks of age. Since isolated cryptorchidism is the most prevalent inherited disorder of the reproductive system reported in dogs, it would be very helpful to have a DNA test to detect carriers of the causative mutations. The remainder of this text refers only to isolated cryptorchidism.

Based on the few pedigree studies in dogs and experimental studies in other animals, testis descent in the dog could be regulated by at least 3 known genes, as well as others that are presently unknown. Mutations in such genes impair the ability of the testes to descend, resulting in cryptorchidism. Delayed descent of the testes may be a less severe form of cryptorchidism, as it shown in some mouse studies. It has been shown in other animals, such as pigs and goats, that the prevalence of cryptorchidism in herds can be reduced over time by selecting against this trait. That is, cryptorchid animals and male and female parents of cryptorchid animals were not used as breeding stock. This approach has not been used extensively in purebred dogs. However, if both male and female carriers could be identified by a practical test, then one could more easily avoid producing affected offspring.

Bilaterally cryptorchid dogs have no testes in the scrotum and are sterile. Unilaterally cryptorchid dogs have one testis descended, and while of lower fertility, can reproduce. An undescended testis may lie within the inguinal (groin) area or within the abdomen and has an increased risk of developing tumors. Additionally, use of affected dogs as breeding stock can eventually lead to increasing numbers of unilaterally and bilaterally cryptorchid dogs in the line or breed. Therefore neutering of affected dogs (surgical removal of both testes) is recommended. To prevent surgically corrected cryptorchid dogs from being deceptively presented as normal, the American Veterinary Medical Association states that it is unethical for a veterinarian to surgically correct this condition without also neutering the animal. Although medical treatments have been proposed for this condition in the dog, there is no evidence that any are efficacious. It is important to note that neither surgery nor medical treatment will alter the affected dog’s genetic makeup. Thus, reproduction from affected dogs and medical treatment of affected dogs may not be in the long term best interest of the breeder, or the breed. Also, breeding of animals with late descending testes may produce more with this condition, and worse, dogs in which the testes fail to descend at all.

Our laboratory is collaborating with other investigators to identify mutations that cause cryptorchidism in dogs. We have not yet found mutations causing canine cryptorchidism, and need to examine DNA from more affected dogs, their related family members, and dogs of several breeds. All participants in our studies are purebred dogs, but their identity and that of their owners is held in strict confidence. Using DNA markers, linkage analysis and association studies, we are presently working to identify the chromosome location of genes responsible for canine cryptorchidism. Our final goal is to produce practical tests to easily identify male and female carriers of mutations that cause cryptorchidism. This will allow breeders to avoid production of cryptorchid offspring while maintaining the desirable traits in their line and breed.

Genes involved in testis descent and cryptorchidism, based on other animal studies
Testis descent is a complex developmental process likely to involve several genes, including those directly controlling testosterone synthesis, the androgen receptor (AR), insulin-like factor 3 (INSL3) and its receptor (GREAT) and calcitonin gene-related peptide (CGRP). For example, any genes encoding enzymes in the steroidogenic pathway leading to testosterone production or stimulating INSL3 secretion could theoretically be involved. Mutations affecting factors listed above account for only a small percentage of human cryptorchidism, so additional genes are likely to be involved, and none has been identified as causative of canine cryptorchidism.
 


Vicki Meyers-Wallen

Contact Information:
Office: 607-256-5683
Fax: 607-256-5608
E-mail: vnm1@cornell.edu