Genetics of sexual differentiation and anomalies in dogs and cats

Normal mammalian sexual differentiation is dependent upon the successful completion of a series of steps that are under genetic control. These steps are marked by three consecutive events-establishment of chromosomal sex, gonadal sex and phenotypic sex. Chromosomal sex is normally established at fertilization. A gene located on the Y chromosome (Tdy) encodes a protein, the testis-determining factor, that is the genetic switch for male development. Testicular development establishes male gonadal sex. Two testicular secretions are responsible for masculinization of the phenotype: Müllerian inhibiting substance causes the Müllerian duct system to regress; testosterone allows development of the vas deferens and epididymides from the Wolffian ducts. Testosterone is metabolized to dihydrotestosterone in cells of the urogenital sinus, genital tubercle, and genital swellings, stimulating formation of the prostate and urethra, the penis, and the scrotum, respectively. In the absence of the Y chromosome and the Tdy gene, the default pathway to female gonadal sex is initiated. The gonadal anlagen develops into an ovary, establishing female gonadal and phenotypic sex. Abnormalities in sexual differentiation are classified by the initial step, as far as is known, at which development differs from normal. Anomalies are categorized as errors in chromosomal, gonadal or phenotypic sex. Reported abnormalities of genetic sex in the dog and cat include abnormalities in chromosomal number or structure, such as the XXY and XO syndromes, chimaeras and mosaics. Abnormalities of gonadal sex include XX sex reversal in the dog, which is inherited as an autosomal recessive trait with phenotypic expression limited to dogs with an XX chromosome constitution. Abnormalities of phenotypic sex include testicular feminization syndrome (TFM) in the cat and persistent Müllerian duct syndrome (PMDS) in the dog. In complete testicular feminization, the androgen receptor is absent or non-functional. Affected individuals have a normal male karyotype (XY) and bilateral testes, but androgen-dependent masculinization is completely absent. As in other species, TFM in the cat is likely to be inherited as an X-linked trait. PMDS in the miniature schnauzer is inherited as an autosomal recessive trait with expression limited to homozygous males. PMDS-affected male dogs have a normal male karyotype (78,XY), bilateral testes, and a complete Müllerian duct system (oviducts, uterus, cervix and cranial vagina). Current studies support the hypothesis that target organ resistance, possibly a mutation in the gene for the MIS receptor, is responsible.