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Biomedical subjects

G A Rappold

Publications and source records attributed to G A Rappold.

At least 55 records · Page 3Linked to original sources
PubMed1997

Abnormal XY interchange between a novel isolated protein kinase gene, PRKY, and its homologue, PRKX, accounts for one third of all (Y+)XX males and (Y-)XY females.

XX males and XY females have a sex reversal disorder which can be caused by an abnormal interchange between the X and the Y chromosomes. We have isolated and characterized a novel gene on the Y chromosome, PRKY. This gene is highly homologous to a previously isolated gene from Xp22.3, PRKX, and represents a member of the cAMP-dependent serine threonine protein kinase gene family. Abnormal interchange can occur anywhere on Xp/Yp proximal to SRY. We can show that abnormal interchange happens particularly frequently between PRKX and PRKY. In a collection of 26 XX males and four XY females, between 27 and 35% of the interchanges take place between PRK homologues but at different sites within the gene. PRKY and PRKX are located far from the pseudoautosomal region where XY exchange normally takes place. The unprecedented high sequence identity and identical orientation of PRKY to its homologous partner on the X chromosome, PRKX, explains the high frequency of abnormal pairing and subsequent ectopic recombination, leading to XX males and XY females and to the highest rate of recombination outside the pseudoautosomal region.

Aneuploidy↗
PubMed1997

Molecular studies of an X;Y translocation chromosome in a woman with deletion of the pseudoautosomal region but normal height.

A translocation chromosome in a woman with the karyotype 46,X,der(X)t(X;Y)(p22.3; q11.2) was investigated by FISH and STS analysis with molecular probes derived from the sex chromosomes. Due to the partial deletion of the short arm pseudoautosomal region (PAR1) from DXYS14 to DXYS147 in the translocation chromosome, the proband is hemizygous for the gene responsible for growth control (SS) located in this region, yet does not show growth retardation. Molecular analysis of the Yq arm of the translocation chromosome revealed the presence of markers DYS273 to DYS246 harboring the hypothesized growth control gene critical region (GCY) on Yq, thereby placing the deletion breakpoint between markers DYS11 and DYS273. These results suggest that the Y-specific growth gene GCY on Yq compensates for the missing growth gene SS on Xp22.3.

Abnormalities, Multiple↗
PubMed1995

A cluster of sulfatase genes on Xp22.3: mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy.

X-linked recessive chondrodysplasia punctata (CDPX) is a congenital defect of bone and cartilage development characterized by aberrant bone mineralization, severe underdevelopment of nasal cartilage, and distal phalangeal hypoplasia. A virtually identical phenotype is observed in the warfarin embryopathy, which is due to the teratogenic effects of coumarin derivatives during pregnancy. We have cloned the genomic region within Xp22.3 where the CDPX gene has been assigned and isolated three adjacent genes showing highly significant homology to the sulfatase gene family. Point mutations in one of these genes were identified in five patients with CDPX. Expression of this gene in COS cells resulted in a heat-labile arylsulfatase activity that is inhibited by warfarin. A deficiency of a heat-labile arylsulfatase activity was demonstrated in patients with deletions spanning the CDPX region. These data indicate that CDPX is caused by an inherited deficiency of a novel sulfatase and suggest that warfarin embryopathy might involve drug-induced inhibition of the same enzyme.

Abnormalities, Drug-Induced↗
PubMed1995

High-density physical mapping of a 3-Mb region in Xp22.3 and refined localization of the gene for X-linked recessive chondrodysplasia punctata (CDPX1).

The study of patients with chromosomal rearrangements has led to the mapping of the gene responsible for X-linked recessive chondrodysplasia punctata (CDPX1; MIM 302950) to the distal part of the Xp22.3 region, between the loci PABX and DXS31. To refine this mapping, a yeast artificial chromosome (YAC) contig map spanning this region has been constructed. Together with the YAC contig of the pseudo-autosomal region that we previously established, this map covers the terminal 6 Mb of Xp, with an average density of 1 probe every 100 kb. Newly isolated probes that detect segmental X-Y homologies on Yp and Yq suggest multiple complex rearrangements of the ancestral pseudoautosomal region during evolution. Compilation of the data obtained from the study of individuals carrying various Xp22.3 deletions led us to conclude that the CDPX disease displays incomplete penetrance and, consequently, to refine the localization of CDPX1 to a 600-kb interval immediately adjacent to the pseudoautosomal boundary. This interval, in which 12 probes are ordered, provides the starting point for the isolation of CDPX1.

Base Sequence↗
PubMed1995

ANT3 and STS are autosomal in prosimian lemurs: implications for the evolution of the pseudoautosomal region.

Comparative in situ hybridization in various primate species has revealed a pseudoautosomal location for the human ANT3 gene and an X-specific location for the steroid sulfatase (STS) gene throughout the higher primate species up to the New World monkeys. However, ANT3 and STS map together on an autosome of two prosimian species of the genus Lemur and Eulemur. These results suggest an autosome-to-X/Y translocation after the simians radiated from the prosimians, resulting in a pseudoautosomal location of genes such as ANT3 and STS. In simian primates, STS then became X-specific by a pericentric inversion in the Y chromosome followed by mutational inactivation of the Y allele.

Animals↗
PubMed1994

A patient with an interstitial deletion in Xp22.3 locates the gene for X-linked recessive chondrodysplasia punctata to within a one megabase interval.

A male patient carrying an interstitial deletion in Xp22.3 and affected by Kallmann syndrome, X-linked ichthyosis and mental retardation, but without chondrodysplasia punctata or short stature, was investigated with molecular probes from the distal Xp22.3 region. By means of a novel probe, M115, from the relevant region, the distal deletion breakpoint was shown to be between 3.18 and 3.57 Mb from Xptel. As the patient is not affected by X-linked recessive chondrodysplasia punctata, the gene for this disease can therefore be located to within an interval of less than one megabase proximal to the pseudoautosomal boundary. If the chondrodysplasia punctata gene is associated with a CpG island, this leaves only two islands at 2760 and 3180 kb from the Xp telomere as the most promising candidate sites for this gene.

Chondrodysplasia Punctata↗
PubMed1994

Double crossover in the human Xp/Yp pseudoautosomal region and its bearing on interference.

Most models on crossover and crossover interference have assumed that the intensity of interference depends inversely on the physical distance separating the respective intervals. The possibility, however, also exists that interference depends on genetic rather than on physical distance. As the human pseudoautosomal region (PAR) on Xp/Yp is physically small, yet genetically a hot spot of recombination in male meiosis, studies on the existence of multiple crossover events may be particularly useful in addressing the question of interference. Our results demonstrate for the first time a double crossover during male meiosis in the human PAR on Xp/Yp. The occurrence of a single obligatory recombination event in this region can, therefore, no longer be taken as a dogma. However, double crossover events seem to remain exceptional and, thus, the model originally suggested by Burgoyne remains globally correct. As both recombination events can be localized within a narrow range of physical distance, theories describing interference due to steric hindrance may have to be reconsidered. This finding may, therefore, have general implications for our understanding of the mechanism of positive and negative crossover interference in mammalian genomes and may be interesting especially for linkage mapping where double recombinations in small intervals tend to be considered as genotyping errors.

Base Sequence↗
PubMed1993

The immunoglobulin kappa locus: polymorphism and haplotypes of Caucasoid and non-Caucasoid individuals.

The immunoglobulin kappa locus has previously been characterized by comparing the restriction patterns of the DNA of 23 Caucasoid individuals and defining various polymorphisms and haplotypes. This study has now been extended to a group of 28 Blacks and another group of 13 individuals of different ethnic origins. The predominant haplotype of the Caucasoid group, called haplotype N, was also found frequently in the other groups. Some of the restriction fragment length polymorphism markers typical of haplotype G, on the other hand, were seen 2-3 times more frequently in the black than in the Caucasoid group. Haplotype 11, which is characterized by the absence of about half of the variable gene segments (V kappa) and which had been observed in 3 out of 46 Caucasoid alleles, has been found twice in the 82 alleles of the two new groups. A number of new polymorphisms was detected and new haplotypes were defined, although the structure of the immunoglobulin kappa locus seems generally to be well conserved among different populations.

Alleles↗
PubMed1993

The pseudoautosomal regions of the human sex chromosomes.

In human females, both X chromosomes are equivalent in size and genetic content, and pairing and recombination can theoretically occur anywhere along their entire length. In human males, however, only small regions of sequence identity exist between the sex chromosomes. Recombination and genetic exchange is restricted to these regions of identity, which cover 2.6 and 0.4 Mbp, respectively, and are located at the tips of the short and the long arm of the X and Y chromosome. The unique biology of these regions has attracted considerable interest, and complete long-range restriction maps as well as comprehensive physical maps of overlapping YAC clones are already available. A dense genetic linkage map has disclosed a high rate of recombination at the short arm telomere. A consequence of the obligatory recombination within the pseudoautosomal region is that genes show only partial sex linkage. Pseudoautosomal genes are also predicted to escape X-inactivation, thus guaranteeing an equal dosage of expressed sequences between the X and Y chromosomes. Gene pairs that are active on the X and Y chromosomes are suggested as candidates for the phenotypes seen in numerical X chromosome disorders, such as Klinefelter's (47,XXY) and Turner's syndrome (45,X). Several new genes have been assigned to the Xp/Yp pseudoautosomal region. Potential associations with clinical disorders such as short stature, one of the Turner features, and psychiatric diseases are discussed. Genes in the Xq/Yq pseudoautosomal region have not been identified to date.

Chromosome Mapping↗
PubMed1993

Genetic map of the human pseudoautosomal region reveals a high rate of recombination in female meiosis at the Xp telomere.

This paper describes the genetic map of the pseudoautosomal region bounded by the telomere of the short arms of the X and Y chromosomes. In males, meiotic exchange on Xp/Yp is confined to this region, leading to highly elevated recombination rates. The map was constructed using 11 pseudoautosomal probes (six of which are new) and typing individuals from 38 CEPH families. All markers have been physically mapped, thus providing the opportunity to compare genetic distance to physical distance through all intervals of the map. This comparison reveals an unexpected high rate of recombination in female meiosis between loci DXYS20 and DXYS78, within 20-80 kb from the telomere. Within this telomere-adjacent region no differences in male and female recombination rates are seen. Furthermore, data from this genetic map support the hypothesis of a linear gradient of recombination across most of the region in male meiosis and provide densely spaced anchor points for linkage studies especially in the telomeric portion of the pseudoautosomal region.

Alleles↗
PubMed1992

Pseudoautosomal repeat displays higher variability in blacks than in Caucasians.

DNA patterns from a pseudoautosomal variable number tandem repeat-like minisatellite (locus DXYS20) were compared in two samples: a Caucasian and a Black sample. We defined 3 types of DNA patterns named A, B and C, and found that these patterns have different frequencies in the Caucasian and Black groups. A set of alleles (the C group) in 48% of the Black sample is not found in the Caucasian sample. We also found a greater degree of fragment-size variability among Black individuals than among those of Caucasian origin. The large degree of ethnic variation indicates that this locus will be useful in population genetic studies.

Animals↗
PubMed1992

Assignment of the human homologue of the mouse t-complex gene TCTE3 to human chromosome 6q27.

The gene TCTE3 from the mouse t-complex region is expressed specifically in testicular germ cells. It maps in the central subregion of the t-complex on mouse chromosome 17 containing loci involved in transmission ratio distortion and male sterility. In this study, somatic cell hybrid lines have been used to map the human homologue, TCTE3, to the long arm of chromosome 6. CISS hybridization with the human lambda clone h117 refined this chromosome assignment to the very distal position of chromosome 6q27, thus providing further evidence that loci from the t-complex of mouse chromosome 17 can map to opposite arms of human chromosome 6.

Animals↗
PubMed1992

Physical mapping of 14 new DNA markers isolated from the human distal Xp region.

We have isolated 14 new DNA markers from the human Xpter-Xp21 region distal to the Duchenne muscular dystrophy gene by targeted cloning, employing two somatic cell hybrids containing this region as their sole human material. High-resolution physical localization of these markers within this region was obtained by hybridization to two mapping panels consisting of DNA from patients carrying various translocations and deletions in distal Xp. Five markers were assigned to the pseudoautosomal region where their position on the long-range map of this region was further determined by pulsed-field gel electrophoresis. The other nine markers map to the X-specific region. Informative TaqI restriction fragment length polymorphisms were observed for four loci. One of these represents a region-specific low-copy repeated element. These 14 new markers represent useful tools for the understanding of distal Xp deletion and translocation mechanisms and for the positional cloning of disease genes in the region.

Blotting, Southern↗
PubMed1988

A long range restriction map of the pseudoautosomal region by partial digest PFGE analysis from the telomere.

The analysis of partial digestion products extending from the telomere of the human X and Y chromosomes, visualised by hybridisation to a probe located close to the telomere, was used to establish a restriction map of the pseudoautosomal region. In this highly polymorphic region with a 10-fold elevated recombination frequency in males we identified site or methylation differences between 7 different in male and female cell lines and tissues, and derived an estimate of the size of the pseudoautosomal region of approximately 3 Megabases by comparing X and Y chromosomes. This size correlates well with previous estimates based on genetic arguments and argues against a strongly enhanced rate of exchange near telomeres in general. We identified a CpG rich and hypomethylated region within 500 kbp from the telomere, which might reflect structural features of mammalian telomeres, and a small number of (additional) CpG islands, which might represent candidate genes for the Turner phenotype in XO females.

Animals↗
PubMed1987

Identification of a testis-specific gene from the mouse t-complex next to a CpG-rich island.

We have used an approach based on the observation of CpG-rich regions near the 5' end of many genes to screen a panel of cosmids derived from the t-complex and tested candidate sequences for evidence of transcription in a number of different mouse tissues. One gene so identified is expressed specifically in testicular germ cells and maps to a subregion of the t-complex also containing loci involved in transmission ratio distortion and male sterility. The transcript is first detected during the pachytene stage of the first meiotic division, but is expressed in highest levels in the later haploid spermatogenic stages. Sequence analysis verified the existence of a CpG-rich element on the 5' end of the gene and predicts a unique protein species with no significant homologies to those previously determined.

Amino Acid Sequence↗