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1.
Choroideremia (McK30310), an X-linked retinal dystrophy, causes progressive night blindness, visual field constriction, and eventual central blindness in affected males by the third to fourth decade of life. The biochemical basis of the disease is unknown, and prenatal diagnosis is not available. Subregional localization of the choroideremia locus to Xq13-22 was accomplished initially by linkage to two restriction-fragment-length polymorphisms (RFLPs), DXYS1 (Xq13-q21.1) and DXS3 (Xq21.3-22). We have now extended our linkage analysis to 12 families using nine RFLP markers between Xp11.3 and Xq26. Recombination frequencies of 0%-4% were found between choroideremia and five markers (PGK, DXS3, DXYS12, DXS72, and DXYS1) located in Xq13-22. The families were also used to measure recombination frequencies between RFLP loci to provide parameters for the program LINKMAP. Multipoint analysis with LINKMAP provided overwhelming evidence for placing the choroideremia locus within the region bounded by DXS1 (Xq11-13) and DXS17 (Xq21.3-q22). At a finer level of resolution, multipoint analysis suggested that the choroideremia locus was proximal to DXS3 (384:1 odds) rather than distal to it. Data were insufficient, however, to distinguish between a gene order that puts choroideremia between DXS3 and DXYS1 and one that places choroideremia proximal to both RFLP loci. These results provide linkage mapping of choroideremia and RFLP loci in this region that will be of use for further genetic studies as well as for clinical applications in this and other human diseases.  相似文献   

2.
Choroideremia (McK30310), an X-linked hereditary retinal dystrophy, causes night-blindness, progressive peripheral visual field loss, and, ultimately, central blindness in affected males. The location of choroideremia on the X chromosome is unknown. We have used restriction fragment length polymorphisms from the X chromosome to determine the regional localization of choroideremia by linkage analysis in families with this disease. One such polymorphic locus, DXYS1, located on the long arm (Xq) within bands q13-q21, shows no recombination with choroideremia at lod = 5.78. Therefore, with 90% probability, choroideremia maps within 9 centiMorgans (cM) of DXYS1. Another polymorphic locus, DXS11, located within Xq24-q26, also shows no recombination with choroideremia, although at a smaller lod score of 1.54 (90% probability limit theta less than 30 cM). This linkage with DXS11, a marker that is distal to DXYS1, suggests that the locus for choroideremia is also distal to DXYS1 and lies between these two markers in the region Xq13-q24. These results provide regional mapping for the disease that may be useful for prenatal diagnosis and, perhaps ultimately, for isolating the gene locus for choroideremia.  相似文献   

3.
Choroideremia: further evidence for assignment of the locus to Xq13–Xq21   总被引:10,自引:3,他引:7  
Summary Choroideremia is an X-linked hereditary retinal dystrophy leading to blindness in early adulthood. RFLP analyses in three Danish families were consistent with close linkage between choroideremia and the locus DXYS1, located at Xq13–Xq21. Measurable linkage was found between choroideremia and DXS17, at Xq22. Furthermore, choroideremia was diagnosed in a boy with an interstitial deletion at Xq13–Xq21, strongly suggesting the assignment of the locus for choroideremia to this region of the X chromosome. The deletion also covered DXYS1, but did not include DXS17.  相似文献   

4.
We have ordered nine polymorphic DNA markers within detailed map of the proximal part of the human X chromosome long arm, extending from band q11 to q22, by use of both physical mapping with a panel of rodent-human somatic hybrids and multipoint linkage analysis. Analysis of 44 families (including 17 families from the Centre d'Etude du Polymorphisme Humain) provided highly significant linkage data for both order and estimation of map distances between loci. We have obtained the following order: DXS1-DXS159-DXYS1-DXYS12-DXS3-(DXS94 , DXS178)-DXYS17. The most probable location of DXYS2 is between DXS159 and DXS3, close to DXYS1 and DXYS12. The high density of markers (nine loci within 30 recombination units) and the improvement in the estimation of recombination frequencies should be very useful for multipoint mapping of disease loci in this region and for diagnostic applications.  相似文献   

5.
Juberg-Marsidi syndrome (McKusick 309590) is a rare X-linked recessive condition characterized by severe mental retardation, growth failure, sensorineural deafness, and microgenitalism. Here we report on the genetic mapping of the Juberg-Marsidi gene to the proximal long arm of the X chromosome (Xq12-q21) by linkage to probe pRX214H1 at the DXS441 locus (Z = 3.24 at theta = .00). Multipoint linkage analysis placed the Juberg-Marsidi gene within the interval defined by the DXS159 and the DXYS1X loci in the Xq12-q21 region. These data provide evidence for the genetic distinction between Juberg-Marsidi syndrome and several other X-linked mental retardation syndromes that have hypogonadism and hypogenitalism and that previously. Finally, the mapping of the Juberg-Marsidi gene is of potential interest for reliable genetic counseling of at-risk women.  相似文献   

6.
Haplotype and multipoint linkage analysis in Finnish choroideremia families   总被引:1,自引:1,他引:0  
Summary Multipoint linkage analysis of choroideremia (TCD) and seven X chromosomal restriction fragment length polymorphisms (RFLPs) was carried out in 18 Finnish TCD families. The data place TCD distal to PGK and DXS72, very close to DXYS1 and DXYS5 (Zmax = 24 at = 0) and proximal to DXYS4 and DXYS12. This agrees with the data obtained from other linkage studies and from physical mapping. All the TCD males and carrier females studied have the same DXYS1 allele in coupling with TCD. In Northeastern Finland, 66/69 chromosomes carrying TCD had the same haplotype at loci DXS72, DXYS1, DXYS4, and DXYS12. The same haplotype is seen in only 15/99 chromosomes not carrying TCD. Moreover, in 71/104 non-TCD chromosomes, the haplotype at six marker loci is different from those seen in any of the 76 TCD chromosomes. This supports the previously described hypothesis that the large Northern Finnish choroideremia pedigrees, comprising a total of over 80 living patients representing more than a fifth of all TCD patients described worldwide, carry the same mutation. These linkage and haplotype data provide improved opportunities for prenatal diagnosis based on RFLP studies.  相似文献   

7.
Summary An insertional translocation into the proximal long arm of the X chromosome in a boy showing muscular hypotony, growth retardation, psychomotor retardation, cryptorchidism, and Pelizaeus-Merzbacher disease (PMD) was identified as a duplication of the Xq21–q22 segment by employing DNA probes. With densitometric scanning for quantitation of hybridization signals, 15 Xq probes were assigned to the duplicated region. Analysis of the duplication allowed us to dissect the X-Y homologous region physically at Xq21 and to refine the assignments of the loci for DXYS5, DXYS12, DXYS13, DXS94, DXS95, DXS96, DXS111, and DXS211. Furthermore, we demonstrated the presence of two different DXYS13, and DXS17 alleles in genomic DNA of our patient, suggesting that the duplication resulted from a meiotic recombination event involving the two maternal X chromosomes.  相似文献   

8.
Summary Two sisters with premature menopause and a small deletion of the long arm of one of their X chromosomes [del (X)(pterq26.3:)] were investigated with polymorphic DNA probes near the breakpoint. The deleted chromosome retained the factor IX (F9) locus and the loci DXS51 (52A) and DXS100 (pX45h), which are proximal to F9. However, the factor VIII (F8) locus was not present, nor were two loci tightly linked to this locus, DXS52 (St14) and DXS15 (DX13) This deletion refines the location of the F9 locus to Xq26 or to the interface Xq26/Xq27, thus placing it more proximally than has been previously reported. The DNA obtained from these patients should be valuable in the mapping of future probes derived from this region of the X chromosome.  相似文献   

9.
Summary We describe a family in which an X-chromosome deletion is segregating with choroideremia, an X-linked recessive condition. The DNA sequences DXYS1 and DXS3, defined by the probes pDP34 and 19.2 respectively, are absent in the affected male (who is also mentally retarded), and hemizygous in his mother and in his carrier sister, who presented early in pregnancy. Analysis of chorionic villus DNA formed the basis of prenatal exclusion of choroideremia in her male fetus. In three female relatives, studied with late-labelling techniques, the deleted X was preferentially inactivated in 86–100% of cells studied. This family confirms the localisation of the choroideremia locus to within Xq1321, and places the loci for anhidrotic ectodermal dysplasia and the X-linked immunodeficiencies outside this region.  相似文献   

10.
During a routine prenatal diagnosis we detected a female fetus with an apparent terminal deletion of an X chromosome with a karyotype 46,X,del(X)(q25); the mother, who later underwent premature ovarian failure, had the same Xq deletion. To further delineate this familial X deletion and to determine whether the deletion was truly terminal or, rather, interstitial (retaining a portion of the terminal Xq28), we used a combination of fluorescence in situ hybridization (FISH) and Southern analyses. RFLP analyses and dosage estimation by densitometry were performed with a panel of nine probes (DXS3, DXS17, DXS11, DXS42, DXS86, DXS144E, DXS105, DXS304, and DXS52) that span the region Xq21 to subtelomeric Xq28. We detected a deletion involving the five probes spanning Xq26-Xq28. FISH with a cosmid probe (CLH 128) that defined Xq28 provided further evidence of a deletion in that region. Analysis with the X chromosome-specific cocktail probes spanning Xpter-qter showed hybridization signal all along the abnormal X, excluding the possibility of a cryptic translocation. However, sequential FISH with the X alpha-satellite probe DXZ1 and a probe for total human telomeres showed the presence of telomeres on both the normal and deleted X chromosomes. From the molecular and FISH analyses we interpret the deletion in this family as 46,X,del(X) (pter-->q26::qter). In light of previous phenotypic-karyotypic correlations, it can be deduced that this region contains a locus responsible for ovarian maintenance.  相似文献   

11.
The CA repeat microsatellite DXS456, with a heterozygosity of 77%, has been localized by multipoint linkage analysis in relation to 20 other genetic markers. DXS456 mapped to a 4.2-cM interval defined by the flanking markers DXS178 and DXS287. The maximum likelihood order of markers, cen-(DXYS1X/DXYS13X/DXYS2X/DXYS12X)-DXS366 -DXS178-DXS456-DXS287-DXS358-DXS267- qter, is favored by odds greater than 1000:1 over the subset of most likely alternative orders. Linkage of DXS456 can be inferred for at least six disease genes that are known to be linked to markers in the region Xq21.31-Xq25 and the marker will serve as an important index point for orienting these and other disease and marker loci in the region.  相似文献   

12.
The study of contiguous gene deletion syndromes by using reverse genetic techniques provides a powerful tool for precisely defining the map location of the genes involved. We have made use of individuals with overlapping deletions producing choroideremia as part of a complex phenotype, to define the boundaries on the X chromosome for this gene, as well as for X-linked mixed deafness with perilymphatic gusher (DFN3). Two patients with deletions and choroideremia are affected by an X-linked mixed conductive/sensorineural deafness; one patient, XL-62, was confirmed at surgery to have DFN3, while the other patient, XL-45, is suspected clinically to have the same disorder. A third choroideremia deletion patient, MBU, has normal hearing. Patient XL-62 has a cytogenetically detectable deletion that was measured to be 7.7% of the X chromosome by dual laser flow cytometry; the other patient, XL-45, has a cytogenetically undetectable deletion that measures only 3.3% of the X chromosome. We have produced a physical map of the X-chromosome region containing choroideremia and DFN3 by using routine Southern blotting, chromosome walking and jumping techniques, and long-range restriction mapping to generate and link anonymous DNA sequences in this region. DXS232 and DXS233 are located within 450 kb of each other on the same SfiI and MluI fragments and share partial SalI fragments of 750 and greater than 1,000 kb but are separated by at least one SalI site. In addition, DXS232, which lies outside the MBU deletion, detects the proximal breakpoint of this deletion. We have isolated two new anonymous DNA sequences by chromosome jumping from DXS233; one of these detects a new SfiI fragment distal to DXS233 in the direction of the choroideremia gene, while the other jump clone is proximal to DXS233 and detects a new polymorphism. These data refine the map around the loci for choroideremia and for mixed deafness with stapes fixation and will provide points from which to isolate candidate gene sequences for these disorders.  相似文献   

13.
Two males with a 46,Y,der(X),t(X;Y)(p22.3;q11) complement were referred independently for evaluation of sterility with azoospermia. Both patients exhibited minimal symptomatology, characterized only by psychological disturbances. Study of X-chromosome breakpoints with pseudoautosomal probes 68B (DXYZ2 elements), 113D (locus DXYS15), and 19B (locus MIC2) indicated in both patients that at least 97% of the X pseudoautosomal sequences are lost. Hybridization with Xp22.3-specific probes DXS283, DXS284, and DXS31 shows that these loci are retained on the rearranged chromosome. Thus, the X-chromosome breakpoints are located close to the proximal boundary of the pseudoautosomal region, between MIC2 and DXS284.  相似文献   

14.
We report a Turner patient aged 22 years with a 45,X/46,X,del(X)(q23) karyotype. Late replication studies showed preferential inactivation of the deleted X chromosome; FISH studies with a probe for total human telomeres showed hybridisation signal in the telomeres on both the normal and the deleted X chromosomes. Microsatellite analysis in the proposita and her family permitted us to conclude to the maternal origin of the deleted X chromosome, and to detect using the marker DXS1106 (Xq22) a probable meiotic recombination event above the breakage point suggesting that the deletion occurred underneath this point.The mild Turner stigmata may be explained by the 45,X cell line, and the gonadal dysgenesis probably by a partial deletion of the gonadal dysgenesis region Xq13-q23 (excluding Xq22).  相似文献   

15.
This paper describes a female infant with microphthalmia with linear skin defects syndrome (MLS) and monosomy for the Xp22 region. Her clinical features included right microphthalmia and sclerocornea, left corneal opacity, linear red rash and scar-like skin lesion on the nose and cheeks, and absence of the corpus callosum. Cytogenetic studies revealed a 45,X[18]/46,X,r(X)(p22q21) [24]/46,X,del(X)(p22)[58] karyotype. Fluorescence in situ hybridization analysis showed that the ring X chromosome was positive for DXZ1 and XIST and negative for the Xp and Xq telomeric regions, whereas the deleted X chromosome was positive for DXZ1, XIST, and the Xq telomeric region and negative for the Xp telomeric region. Microsatellite analysis for 19 loci at the X-differential region of Xp22 disclosed monosomy for Xp22 involving the critical region for the MLS gene, with the breakpoint between DXS1053 and DXS418. X-inactivation analysis for the methylation status of the PGK gene indicated the presence of inactive normal X chromosomes. The Xp22 deletion of our patient is the largest in MLS patients with molecularly defined Xp22 monosomy. Nevertheless, the result of X-inactivation analysis implies that the normal X chromosomes in the 46,X,del(X)(p22) cell lineage were more or less subject to X-inactivation, because normal X chromosomes in the 45,X and 46,X,r(X)(p22q21) cell lineages are unlikely to undergo X-inactivation. This supports the notion that functional absence of the MLS gene caused by inactivation of the normal X chromosome plays a pivotal role in the development of MLS in patients with Xp22 monosomy. Received: 16 December 1997 / Accepted: 25 February 1998  相似文献   

16.
Summary A de novo interstitial deletion (X)(q27.1q27.3), between the loci DXS 105 and F8, has been found in a mentally retarded female. The deleted X chromosome is preferentially early replicating in fibroblasts, B cells and T cells, suggesting that the missing region plays a role in inactivation of the X chromosome. None of the available DNA probes except DXS 98 maps to the deleted region of about 10000kb. The locus FRAXA is either included in the deletion, or located close to the distal break point.  相似文献   

17.
Summary The q26–q28 region of the human X chromosome contains several important disease loci, including the locus for the fragile X mental retardation syndrome. We have characterized new polymorphic DNA markers useful for the genetic mapping of this region. They include a new BclI restriction fragment length polymorphism (RFLP) detected by the probe St14-1 (DXS52) and which may therefore be of diagnostic use in hemophilia A families. A linkage analysis was performed in fragile X families and in large normal families from the Centre d'Etude du Polymorphisme Humain (CEPH) by using seven polymorphic loci located in Xq26-q28. This multipoint linkage study allowed us to establish the order centromere-DXS100-DXS86-DXS144-DXS51-F9-FRAX-(DXS52-DXS15). Together with other studies, our results define a cluster of nine loci that are located in Xq26-q27 and map within a 10 to 15 centimorgan region. This contrasts with the paucity of markers (other than the fragile X locus) between the F9 gene in q27 and the G6PD cluster in q28, which are separated by about 30% recombination.  相似文献   

18.
The locus responsible for X-linked, nonsyndromic cleft palate and/or ankyloglossia (CPX) has previously been mapped to the proximal long arm of the human X chromosome between Xq21.31 and q21.33 in an Icelandic kindred. We have extended these studies by analyzing an additional 14 informative markers in the family as well as including several newly investigated family members. Recombination analysis indicates that the CPX locus is more proximal than previously thought, within the interval Xq21.1-q21.31. Two recombinants place DXYS1X as the distal flanking marker, while one recombinant defines DXS326 as the proximal flanking marker, an interval of less than 5 cM. Each of the flanking markers recombines with the CPX locus, giving 2-point lod scores of Zmax = 4.16 at θ = 0.08 (DXS326) and Zmax = 5.80 at θ = 0.06 (DXYS1X).  相似文献   

19.
We report the results of studies on the characterization of the mutation associated with marked unbalanced expression of the mutant X chromosome in a karyotypically normal girl with Hunter disease (mucopolysaccharidosis type II). Southern analysis of DNA extracted from somatic cell hybrids containing only the mutant X chromosome showed deletion of the Xq27.3-q28 loci: DXS297 (VK23AC), DXS293 (VK16), FRAXA (pfxa3), DXS296 (VK21A), and the 3' end of the iduronatesulfatase (IDS) gene. The flanking loci--DXS52 (St14-1), DXS304 (U6.2), and DXS369 (RN1)--were intact. On the basis of these results, we concluded that the mutation was a simple deletion extending a maximum of 3-5 cM to the centromeric side of the IDS gene. Both Southern analysis of DNA from somatic cell hybrids, using short segments of IDS cDNA, and PCR of reverse-transcribed RNA from cultured skin fibroblasts indicated that the telomeric terminus of the deletion was localized to a region near the middle of the coding sequences of the gene.  相似文献   

20.
Summary In a four-generation family, chondrodysplasia punctata was found in a boy and one of his maternal uncles. These two patients also have short stature, as do all female members of the family. DNA molecular analysis of the pseudoautosomal and Xp22.3-specific loci revealed the presence of an interstitial deletion that cosegregates with the phenotypic abnormalities. The proximal breakpoint of this deletion was located distal to the DXS31 locus and the distal breakpoint in the pseudoautosomal region between DXYS59 and DXYS17. This maps the recessive X-linked form of chondrodysplasia punctata between the proximal boundary of the pseudoautosomal region and DXS31, and an Xp gene controlling growth between DXYS59 and DXS31.  相似文献   

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