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D C Page

Publications and source records attributed to D C Page.

At least 109 records · Page 6Linked to original sources
PubMed1987

The sex-determining region of the human Y chromosome encodes a finger protein.

The presence or absence of the Y chromosome determines whether a mammalian embryo develops as a male or female. In humans, genetic deletion analysis of "sex-reversed" individuals has identified a small portion of the Y chromosome necessary and sufficient to induce testicular differentiation of the bipotential gonad. We report the cloning of a 230-kilobase segment of the human Y chromosome that contains some or all of the testis-determining factor gene (TDF), the master sex-determining locus. The cloned region spans the deletion in a female who carries all but 160 kilobases of the Y. Certain DNA sequences within this region were highly conserved during evolution; homologs occur on the Y chromosomes of all mammals examined. In particular, homologous sequences are found within the sex-determining region of the mouse Y chromosome. The nucleotide sequence of this conserved DNA on the human Y chromosome suggests that it encodes a protein with multiple "finger" domains, as first described in frog transcription factor IIIA. The encoded protein probably binds to nucleic acids in a sequence-specific manner, and may regulate transcription. Very similar DNA sequences occur on the X chromosome of humans and other mammals. We discuss the possibility that the Y-encoded finger protein is the testis-determining factor, and propose models of sex determination accommodating the finding of a related locus on the X chromosome. The presence of similar sequences in birds suggests a possible role not only in the XX/XY sex determination system of mammals, but also in the ZZ/ZW system of birds.

Amino Acid Sequence↗
PubMed1987

A sex chromosome rearrangement in a human XX male caused by Alu-Alu recombination.

Human XX maleness is often due to the presence of Y-specific DNA, resulting from abnormal interchange of terminal parts of the short arms of the X and Y chromosomes. In an XX male, a rearrangement is observed at locus DXYS5, the most proximal Yp locus detected in this patient. Cloning and analysis of the rearranged DNA fragment revealed pseudoautosomal sequences located beyond the breakpoint. We propose that this XX male arose by abnormal crossing over between DXYS5 on the Y chromosome and a pseudoautosomal locus on the X chromosome during paternal meiosis. Sequence analysis of the junction shows that homologous recombination occurred between two Alu sequences from these otherwise nonhomologous regions. The site of recombination is localized to the putative transcription promoter region of the Alu sequences.

Cells, Cultured↗
PubMed1987

Familial premature ovarian failure due to an interstitial deletion of the long arm of the X chromosome.

We describe a family in which four women had menstrual irregularities and a partial deletion of the long arm of the X chromosome (Xq). Three of the four women had premature ovarian failure (at the ages of 24 to 37 years). Chromosome-banding studies initially suggested that a terminal portion of Xq was deleted. However, DNA-hybridization studies showed that an interstitial portion of Xq was deleted and that the affected women had a 46,XX,del(X)(pter-q21.3::q27-qter) karyotype. These findings help clarify the role of Xq in ovarian function and indicate that the accurate description of such abnormalities requires a combination of cytogenetic and DNA-hybridization analysis.

Adult↗
PubMed1987

Linkage, physical mapping, and DNA sequence analysis of pseudoautosomal loci on the human X and Y chromosomes.

The pseudoautosomal region of the human X and Y chromosomes is subject to frequent X-Y recombination during male meiosis. We report the finding of two pseudoautosomal loci, DXYS20 and DXYS28, characterized by highly informative restriction fragment length polymorphisms (RFLPs). The pseudoautosomal character of DXYS20 and DXYS28 was formally demonstrated by comparing their transmission to 45,X and to normal individuals. Studies of the inheritance of these loci reveal that the pseudoautosomal region, though highly recombinogenic, is subject to marked recombinational interference in male meiosis; no double recombinants were observed in 143 triply informative meioses, and the coefficient of coincidence is likely less than 0.45. In female meiosis, linkage of these pseudoautosomal RFLPs to strictly sex-linked RFLPs on the short arm of the X is readily detected; the genetic length of the pseudoautosomal region in female meiosis is at least 4 cM but not more than 18 cM. The genetic map of the human X chromosome is now defined from near the short-arm telomere to band q28 on the long arm. Locus DXYS20, which maps near the X and Y short-arm telomeres, is composed of long tandem arrays of 61-bp repeats. Occasional, seemingly random base-pair substitutions within these arrays of 61-bp repeats, in combination with marked variation in the size of the array, generate the high degree of DNA polymorphism at DXYS20.

Base Sequence↗
PubMed1987

Hypothesis: a Y-chromosomal gene causes gonadoblastoma in dysgenetic gonads.

The role of the human Y chromosome in the etiology of gonadoblastoma, a gonadal neoplasm, is considered and a two-part model is presented. According to this hypothesis: (1) There is a gene on the Y chromosome that strongly predisposes dysgenetic gonads to develop gonadoblastomas (Page, 1986) and (2) this postulated GBY gene (GonadoBlastoma locus on Y chromosome) has some physiological function in normal males. GBY may, for example, function in or prior to spermatogenesis in normal testes. Y-DNA hybridization analysis of individuals with gonadoblastoma and partial deletions of the Y chromosome should be of use in testing this proposal. To date, such studies suggest that GBY maps to the region that includes deletion intervals 4B to 7, i.e. it is located near the centromere or on the long arm of the Y chromosome.

Chromosome Mapping↗
PubMed1987

An XXX male resulting from paternal X-Y interchange and maternal X-X nondisjunction.

A 2-year-old boy was found to have a 47,XXX karyotype. Restriction-fragment-length-polymorphism analysis showed that, of his three X chromosomes, one is of paternal and two are of maternal origin. The results of Y-DNA hybridization were reminiscent of those in XX males in two respects. First, hybridization to Southern transfers revealed the presence in this XXX male of sequences derived from the Y-chromosomal short arm. Second, in situ hybridization showed that this Y DNA was located on the tip of the X-chromosomal short arm. We conclude that this XXX male resulted from the coincidence of X-X nondisjunction during maternal meiosis and aberrant X-Y interchange either during or prior to paternal meiosis.

Child, Preschool↗
PubMed1987

A unique dicentric X;Y translocation with Xq and Yp breakpoints: cytogenetic and molecular studies.

A 32-year-old woman presented with secondary amenorrhea and infertility. She was of normal height and her breasts were well developed, but she had streak gonads; there were no signs of virilization, and she showed no somatic stigmata of Turner syndrome. Chromosome analysis revealed a dicentric X;Y translocation with Xq and Yp breakpoints. Centromeric banding demonstrated a Y centromere and a "suppressed" X centromere. The karyotype of the patient was interpreted as 46,X,t(X;Y)(q22;p11). The Yp breakpoint was confirmed by DNA-hybridization studies with six probes detecting Y-specific sequences. These DNA-hybridization studies were consistent with the presence of the long arm, centromere, and much of the proximal short arm of the Y. The Y-DNA studies of this female also revealed the absence of the distal short arm of the Y chromosome, to which the testis-determining factor has previously been localized.

Adult↗
PubMed1987

A 45,X male with Y-specific DNA translocated onto chromosome 15.

A 20-year-old male patient with chromosomal constitution 45,X, testes and normal external genitalia was examined. Neither mosaicism nor a structurally aberrant Y chromosome was observed when routine cytogenetic analysis was performed on both lymphocytes and skin fibroblasts. Y chromosome-specific single-copy and repeated DNA sequences were detected in the patient's genome by means of 11 different recombinant-DNA probes of known regional assignment on the human Y chromosome. Data indicated that the short arm, the centromere, and part of the long-arm euchromatin of the Y chromosome have been retained and that the patient lacks deletion intervals 6 and 7 of Yq. High-resolution analysis of prometaphase chromosomes revealed additional euchromatic material on the short arm of one of the patient's chromosomes 15. After in situ hybridization with the Y chromosome-specific probe pDP105, a significant grain accumulation was observed distal to 15p11.2, suggesting a Y/15 chromosomal translocation. We conclude that some 45,X males originate from Y-chromosome/autosome translocations following a break in the proximal long arm of the Y chromosome.

Adult↗
PubMed1987

Mapping the H-Y gene.

This paper uses cytotoxic and proliferative T cell clones specific for H-Y and restricted by MHC molecules to type mice and humans inheriting incomplete portions of the Y chromosome. The data have allowed us to map the H-Y antigen gene Hya in mouse to a position closely linked with, but separable from, Tdy on the Sxr fragment and thus presumably to a position of the normal mouse Y chromosome near the centromere. The human H-Y gene maps between deletion intervals 4B and 7, separate from TDF which is on interval 1. We are currently testing cells from a number of additional patients who have inherited different portions of the Y chromosome to pinpoint the mapping more closely. It is of interest that in mouse a Y-linked gene controlling spermatogenesis (Spy) maps near Hya on the Sxr fragment: they could be the same or closely linked genes. In man, a gene controlling spermatogenesis maps to Yq and the data so far do not exclude that it could be coincident with the H-Y gene.

Animals↗
PubMed1986

Chromosome Y-specific DNA is transferred to the short arm of X chromosome in human XX males.

Y-chromosomal DNA is present in the genomes of most human XX males. In these cases, maleness is probably due to the presence of the Y-encoded testis-determining factor (TDF). By means of in situ hybridization of a probe (pDP105) detecting Y-specific DNA to metaphases from three XX males, it was demonstrated that the Y DNA is located on the tip of the short arm of an X chromosome. This finding supports the hypothesis that XX maleness is frequently the result of transfer of Y DNA, including TDF, to a paternally derived X chromosome.

Cells, Cultured↗
PubMed1986

Regional assignments of three polymorphic DNA segments on human chromosome 15.

Hybridization of probe pDP151 (locus D15S2) to genomic human DNAs digested with EcoRI revealed allelic restriction fragments 9 and 11 kilobase-pairs (kb) in length. Hybridization of pDP151 to EcoRI-digested DNAs from 21 Chinese hamster X human hybrid cell clones containing different subsets of human chromosomes demonstrated cosegregation of the 9 and 11 kb EcoRI fragments with human chromosome 15. D15S2 and two other polymorphic loci previously mapped to chromosome 15--D15S1 and D15S6--were localized to specific regions on human chromosome 15. Eight Chinese hamster X human somatic cell hybrid clones derived from a human donor heterozygous for a balanced translocation between chromosomes 15 and 22 [t(15;22)(q14;q13.3); Oliver et al, Cytogenet Cell Genet 22:503-510, 1978] were studied. After digestion of human and hybrid DNAs with HindIII and Southern blotting, pDP151 (D15S2) and pMS1-14 (D15S1) hybridized to fragments of 4 and 4.5 kb, respectively. Further, pMS1-14 (D15S1) and p9-1a (D15S6) hybridized to EcoRI fragments of 3.5 and 3.2 kb. All fragments cosegregated with the der(22) derivative chromosome containing region 15q14----15qter. In situ hybridization of these probes to normal human chromosomes mapped the corresponding loci with greater precision: D15S1 to 15q15----15q21, D15S2 to 15q15----15q22, and D15S6 to 15q22----15q24.

Chromosome Mapping↗
PubMed1986

Molecular detection of a translocation (Y;15) in a 45,X male.

A 45,X male individual was shown to have a translocation of Y-chromosome material to the short arm or proximal long arm of chromosome 15. This translocation was detected by genomic DNA blotting and in situ hybridization with Y-chromosome-specific DNA probes.

Chromosome Banding↗
PubMed1986

Small deletions of the short arm of the Y chromosome in 46,XY females.

Structural anomalies of the sex chromosomes provide a means to study the location of genes responsible for sex determination. Recently, a type of sex reversal in humans, the 46,XX male, was shown to result in some cases from translocation of Y chromosome material to the X chromosome. In the present report, another type of sex reversal, the 46,XY female, is shown to result, in two cases, from small deletions of the short arm of the Y chromosome. Prometaphase chromosome analysis showed a 46,X,Yp- karyotype. Several Y chromosome-specific DNA probes were found to be deleted in the two female patients. DNA analysis showed that the two deletions were different but included a common overlapping region likely to be essential for male determination.

Chromosome Deletion↗
PubMed1986

A deletion map of the human Y chromosome based on DNA hybridization.

The genomes of 27 individuals (19 XX males, two XX hermaphrodites, and six persons with microscopically detectable anomalies of the Y chromosome) were analyzed by hybridization for the presence or absence of 23 Y-specific DNA restriction fragments. Y-specific DNA was detected in 12 of the XX males and in all six individuals with microscopic anomalies. The results are consistent with each of these individuals carrying a single contiguous portion of the Y chromosome; that is, the results suggest a deletion map of the Y chromosome, in which each of the 23 Y-specific restriction fragments tested can be assigned to one of seven intervals. We have established the polarity of this map with respect to the long and short arms of the Y chromosome. On the short arm, there is a large cluster of sequences homologous to the X chromosome. The testis determinant(s) map to one of the intervals on the short arm.

Chromosome Banding↗
PubMed1986

The origin of 45,X males.

Maleness in association with the karyotype 45,X is a very rare and hitherto unexplained condition previously described in only four or five patients. This study was carried out to determine whether such males might actually possess Y-chromosomal material. Of the two 45,X males studied, one was found to be a low-grade mosaic with a 46,XY karyotype in less than 3% of fibroblasts; all lymphocytes karyotyped were 45,X. Fibroblast DNA from this individual was found to contain Y-specific repeated sequences in 1%-3% the amount observed in the father, consistent with mosaicism for a 46,XY cell line. No Y-specific repeated sequences were detected in the other patient, in whom all mitoses were 45,X. In neither patient were there detectable amounts of any of the single-copy Y-specific DNA sequences for which we tested. Studies of Xg blood groups and of X-linked restriction fragment length polymorphisms indicated that the single X chromosome was of maternal origin in both 45,X male probands. In contrast to the situation in XX males, we can exclude paternal X-Y interchange as the etiology in the cases described here. Our findings are compatible with mosaicism being the explanation of at least some "45,X" males.

DNA Restriction Enzymes↗
PubMed1984

The parental origin of X chromosomes in XX males determined using restriction fragment length polymorphisms.

The inheritance of several X-linked restriction fragment length polymorphisms ( RFLPs ) is examined in seven 46,XX males and their immediate relatives. The XX males are shown to have inherited a paternal and a maternal RFLP allele in each of the five (of seven) families in which these X-linked markers are informative. In the other two families, a maternal X-chromosomal contribution is demonstrated, but a paternal contribution cannot be determined. We conclude that most, if not all, XX males inherit one paternal and one maternal X chromosome. A segment of single-copy DNA specific to the short arm of the Y chromosome is found to be absent from the genomes of eight XX males. In one of these XX males, an Xp-Yp translocation had previously been inferred from chromosome-banding studies. Our findings argue against mosaicism involving a Y-containing cell line in the XX males examined here, but they do not exclude an X-Y (or Y-autosome) translocation during paternal meiosis. If such a translocation has occurred, the translocation product received by the XX males does not include the Yp-specific sequence tested here.

Alleles↗