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SRY-negative XX sex reversal (XXSR) is a type of hermaphroditism that affects a number of dog breeds (at least 15 breeds), including the Kerry Blue Terrier. It is currently believed to be inherited as a simple autosomal recessive defect. This article answers some questions about the causes and expression of XX sex reversal.
What is a karyotype?
A karyotype is an inventory of the chromosomes in an organism. Dogs have 78 chromosomes. Half of these come from the dam and half from the sire. 76 of these chromosomes occur as homologous pairs, meaning that they are similar in appearance and in the general content and order of the genes they contain. The other two chromosomes are the sex chromosomes, the X and Y chromosomes. Normally a male has a karyotype of 78, XY and a female has a karyotype of 78, XX. Only dogs with a female karyotype (78,XX) and two mutant genes for the disorder are affected with Sry-negative XX sex reversal. Carriers have only one mutant gene for the defect. Carrier males (78,XY) and females (78,XX) develop normally.
What causes XX sex reversal?
XX sex reversal is caused by an error in the sexual development of the embryo. Normal sexual development is controlled by a complex genetic program that proceeds through three major stages, establishing chromosomal sex, then gonadal sex, then phenotypic sex. Chromosomal sex is established at fertilization. This step is accomplished normally in XXSR affected females, which have a karyotype of 78, XX. The next step, establishment of gonadal sex, is where the abnormality occurs as a result of this genetic defect. Instead of forming normal ovaries, affected bitches form gonads which are partially or entirely composed of testicular tissue. As a result,the subsequent step, establishment of phenotypic sex the development of normal sexual organs, appearance and fertility is also disrupted.
What are the signs of XXSR?
The external signs of XXSR range from subtle to extreme. In some cases the affected bitch appears almost normal in the structure and placement of external genitals. In other cases, the vulva is shifted forward (toward the head) into a position intermediate between that of normal vulva and normal prepuce. In some cases a small penis-like organ may be present. Still other cases present looking like virtually normal males, but if one looks carefully, the prepuce is usually displaced toward the tail and the urinary orifice is displaced along the shaft of the penis and not at the tip. They frequently are bilaterally cryptorchid and are also sterile. Pictures are available on Dr. Meyers-Wallen's web site if you want to see some of the ways XXSR can change anatomy.
Internally, gonadal development is changed. Instead of normal ovaries, affected bitches will have gonads that consist partly or completely of testicular tissue. In most cases, this results in infertility. Lack of heat cycles and infertile cycles can be a clue to the presence of XXSR. In addition, XXSR can cause malformations that impair urine drainage from the bladder and affected bitches can be prone to chronic bladder infections. Surgical repairs are required in these cases.
How is XXSR inherited?
XXSR has been shown to be inherited as an autosomal recessive trait in the American Cocker Spaniel and a few other breeds. Not enough samples have been obtained from Kerry Blue Terriers to definitively show that this is the mode of inheritance in our breed; however, it is considered to be inherited in this fashion by specialists. Remember, in an autosomal recessive trait, both parents must carry the defect in order to produce an affected offspring. Statistically, two carrier parents, where each carries only one mutant gene for the defect, will produce 25% normal, 50% carrier, and 25% affected offspring. The actual percentage of XXSR-affected individuals is much lower than 25% because only affected females show any signs of the disorder. We would expect that 12.5% of the offspring of two carriers would be detectably affected. However, since the signs of the disorder can be subtle in some cases, they may not be noticed and the bitch may not be recognized as a hermaphrodite. Therefore, with XXSR the number of affected offspring produced by carrier parents appears to be less than 12.5%.
How important is XXSR as an inherited trait?
XXSR is of moderate importance as a genetic disorder, when ranked according to a hierarchy of disagreeability of a genetic trait. It is not lethal, chronically painful (unless chronic bladder infections occur and are not treated), severely disfiguring, maiming or otherwise destructive of the functionality of the animal (except breeding), nor does it require life-long treatment. However, it does require surgical correction spaying of affected females and this surgery may be complicated, depending upon the extent to which development is abnormal. Some cases require the services of a specialist to remove the affected sexual organs and to correct problems in the urinary tract that lead to chronic cystitis and possible urinary incontinence. Costs to the owner are therefore increased and surgical risks to the bitch are also increased. There is also a risk that urinary incontinence may be chronic which is a nuisance to the owner and a health risk to the dog. In addition, if the affected female was an intended brood bitch, the breeder has lost his or her investment, as most affected females are sterile. In the rare case that the affected bitch is fertile, serious consideration must be given to the fact that all of her offspring will be carriers of the defect.
I've heard of XX males and XX true hermaphrodites. Are these disorders different from XX sex reversal?
No, XX males and XX true hermaphrodites are both types of XX sex reversal. XX sex reversal refers to karyotypic females (78, XX) which have some degree of testes development. The amount of testes development is variable. If both gonads are entirely testes, then the individual is an XX male. If the gonads are a mixture of ovarian and testicular tissue, then the individual is an XX true hermaphrodite. The latter form of the disorder is the most common.
What is SRY?
SRY is the name of a gene that occurs on the Y chromosome. It normally starts the genetic program that results in the development of male gonads and male phenotype. Because the gene resides on the Y chromosome, only XY individuals normally develop male characteristics. Sometimes, SRY is involved in a translocation event. Translocation occurs when a gene normally found on one chromosome moves to an entirely different chromosome. Some cases of XXSR result when SRY moves to another chromosome and is therefore present in an XX (female) embryo. SRY is still functional and starts the male development program in the female embryo. All mouse cases and 80% of human cases of XXSR are caused by this type of translocation event.
Why is the type of XXSR found in dogs described as SRY-negative?
Originally, it was thought that all cases of XXSR were caused by SRY gene translocation to another chromosome. However, 20% of human cases and all dog cases of XXSR lack the SRY gene on any of the chromosomes present. This means that there is a type of XXSR lacking or negative for SRY gene and that a defect involving some other gene in the male development program is involved. The genetic program for male development involves a number of genes which become active at different stages of embryo development. In the normal female dog, these genes remain dormant because SRY is not present to start them functioning. It's believed that in XXSR affected bitches some genetic abnormality is present that activates one of these dormant genes in the absence of SRY.
If XXSR in Kerries is an autosomal recessive trait, why are there no affected males?
Actually, there are "affected" males, in the sense that they have both defective copies of the gene (i.e., they are homozygous for the defective allele). They don't show any abnormalities, though, since they have the SRY gene on their Y chromosome. Thus, the genetic program for male development is running anyway and the fact that one of the genes in the pathway isactivated in a different fashion is irrelevant. The danger of this situation is that all offspring of such an affected male will get a copy of the defective gene. If mated with a normal female, all offspring will be carriers. If mated with a carrier female, 50% of the offspring will be carriers and 50% will be affected (25% affected females and 25% homozygous males). If this affected dog was a popular stud, you can imagine how quickly the trait could spread throughout the breed!
Is there a test to detect XXSR in breeding stock?
There is no test at this time to detect XXSR carriers. However, Dr. Meyers-Wallen at the Baker Animal Institute for Animal Health (Cornell University) is working on a DNA linkage test with samples from American Cocker Spaniels. Once the test is developed for Cockers, she will see if the test works on the Kerry samples she currently has. If the same genetic defect causes XXSR in both Kerries and Cockers, we will have a DNA test available for our breed. If the defect in Kerries is different, more work would have to be done to develop a test.
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I am very grateful to Dr. Meyers-Wallens <firstname.lastname@example.org> for her helpful comments on this article and discussions about the disorder.