Biomedical subjects
Publications and source records attributed to G C Koo.
Serological analysis of white blood cells from the members of a family of American cocker spaniels indicates that a form of abnormal sexual development, in which individuals with a female karyotype have testes or ovotestes, is caused by anomalous transmission of male-determining H-Y genes.
The autosomal dominant gene polled (P) causes hornlessness in goats. Chromosomal females (XX) that are P/P homozygotes develop testes or ovotestes. Thus with respect to its testis-determining properties, P or a closely linked gene acts as an autosomal recessive. Polled intersex goats are H-Y+. This finding is consistent with the view that there may be a cluster of testis-determining H-Y genes on the Y chromosome, and that translocation of a subcritical portion of these genes may generate a recessive mode of sex determination.
Maleness is normally inherited as a dominant trait (a single copy of the Y chromosome induces testicular differentiation of the embryonic gonad), but our genealogic study of three XX males in one pedigree indicated an autosomal recessive mode of male inheritance. Subsequent study revealed the presence of H-Y antigens in the three XX males and in their mothers, and suggested that excess H-Y may be found in the fathers. Inasmuch as H-Y loci have been mapped to the human Y chromosome, these data favor the view that H-Y structural loci comprise a family of testis-determining genes, and that Y autosome (or Y-X) translocation can generate either dominant or recessive modes of XX sex reversal, depending upon the particular portion of H-Y genes transferred.
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The H-Y locus is on the short arm of the human Y chromosome in most individuals but on the long arm in at least one of 17 individuals with structural abnormalities of the Y.
Androgen-insensitive subjects with a 46,XY karotype develop as phenotypic females despite presence of testes. The white blood cells of these females type H-Y antigen-positive indicate that expression of the H-Y cell surface component is androgen-independent.
Evidence that expression of histocompatibility-Y (H-Y) antigen on human cells is determined by a Y-linked gene is provided by data demonstrating that male subjects with two Y chromosomes have higher antigen levels than male subjects with one Y chromosome. The widespread evolutionary conservation of H-Y antigen and its association with the Y chromosome suggest that the antigen has a specific, crucial function. We surmise that this function is the differentiation of the embryonic gonad into whichever mature gonad, testis or ovary, typifies the heterogametic sex of each species. Of particular interest are individuals whose gonadal sex does not correspond to their somatic genotype. In the present article, we report positive results in the first case of 46,XY pure gonadal dysgenesis (Swyer's syndrome) to be typed for H-Y antigen. This case suggests that the presence of H-Y antigen may not be sufficient to complete masculinization of the embryonic mammalian gonad. Alternatively, a mutant gene may govern expression of a cell surface component which cross reacts with H-Y antigen but which lacks the ability to function in the virilization of the gonad.
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A number of patients with a male phenotype and a female (46XX) karyotype have been described. Although there is little or no evidence for the presence of a Y chromosome in their cells, these individuals resemble patients with Klinefelter syndrome (47XXY). Using a new serological assay for the presence of H-Y antigen, a cell surface component associated with the Y chromosome, we have demonstrated the presence of Y-chromosomal genes in a 46-year-old man with an XX karyotype. In addition, using standard cytological technique, we have located a minor population of XXY cells as well as cells bearing and abnormal chromosome 17 among the blood leukocytes of this individual.
To test the hypothesis that H-Y antigen (present on both somatic and germ cells in normal males but not normal females) is essential for testicular differentiation, we studied four XX males and three XX true hermaphrodites. Blood cells from six subjects and cultured gonadal fibroblasts from a seventh expressed H-Y antigen. Since expression of this antigen requires the presence of a gene normally carried by the Y chromosome, this gene, and perhaps additional Y chromosomal material, should have been present in the genome of these subjects. In one patient this presence is accounted for by a Y-to-X translocation, detectable by chromosome banding. In another a normal Y chromosome was present in a minor population of cells. In the remaining five, no karyotypic abnormality was detectable. Immunologic detection of H-Y antigen is a sensitive test for the presence of the Y chromosome or of its male-determining segment.
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Endocrinologic and serologic studies of a 2-year-old child with the chromosomal complement 46,XX and ambiguous genitalia suggested the preoperative diagnosis of true hermaphroditism. Urinary and serum androgen production in response to human chorionic gonadotrophin was in the range expected for normal males, implying presence of cryptic testicular tissue. Moreover, detection of H-Y antigen, a cell surface component associated with testicular differentiation and coded or regulated by a Y-chromosomal gene, indicated presence of Y-chromosomal material. The diagnosis of true hermaphroditism was confirmed at surgery. Assuming a constant association of H-Y antigen and testicular differentiation is established, human H-Y serology may be an important adjunct to the endocrinologic evaluation of intersex patients. Our studies support the interpretation that a Y-chromosomal translocation too small for cytologic detection accounts for testicular differentiation in 46,XX true hermaphroditism. Expression of H-Y antigen remained positive after castration.
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To determine whether the gene that controls the expression of H-Y ("male") antigen on human cells is Y-linked, we have compared the H-Y antigen level in normal males with that in three males with two Y chromosomes. Leukocytes from one XXYY and two XYY males express more H-Y antigen than leukocytes from normal XY males. We conclude that a structural gene or positive regulatory gene for H-Y antigen is on the human Y chromosome. Testing for the H-Y antigen may be of benefit in patients who have signs of masculinization but who lack an identifiable Y chromosome. Positive results for the H-Y antigen would be tentative evidence that the corresponding region of the Y chromosome was present, perhaps as part of a translocation, despite the absence of a typical Y chromosome.
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Antisera to H-Y (male-specific) antigen were prepared by immunizing female mice with spleen cells from males of the same inbred strain. These antisera were used in mixed hemadsorption and cytotoxicity tests with cells of rats, guinea pigs, rabbits, and humans. The results showed that the H-Y components of all four species are antigenically related to H-Y of the mouse.