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1.
X-linked deafness is a rare cause of hereditary hearing impairment. We have identified a family with X-linked dominant sensorineural hearing impairment, characterized by incomplete penetrance and variable expressivity in carrier females, that is linked to the Xp21.2, which contains the Duchenne muscular dystrophy (DMD) locus. The auditory impairment in affected males was congenital, bilateral, profound, sensorineural, affecting all frequencies, and without evidence of radiographic abnormality of the temporal bone. Adult carrier females manifested bilateral, mild-to-moderate high-frequency sensorineural hearing impairment of delayed onset during adulthood. Eighteen commercially available, polymorphic markers from the X chromosome, generating a 10-15-cM map, were initially used for identification of a candidate region. DXS997, located within the DMD gene, generated a two-point LOD score of 2.91 at theta = 0, with every carrier mother heterozygous at this locus. Recombination events at DXS992 (located within the DMD locus, 3' to exon 50 of the dystrophin gene) and at DXS1068 (5' to the brain promoter of the dystrophin gene) were observed. No recombination events were noted with the following markers within the DMD locus: 5'DYS II, intron 44, DXS997, and intron 50. There was no clinical evidence of Duchenne or Becker muscular dystrophy in any family member. It is likely that this family represents a new locus on the X chromosome, which when mutated results in nonsyndromic sensorineural hearing loss and is distinct from the heterogeneous group of X-linked hearing losses that have been previously described.  相似文献   

2.
Refinement of the locus for non-syndromic sensorineural deafness (DFN2)   总被引:4,自引:0,他引:4  
Cui B  Zhang H  Lu Y  Zhong W  Pei G  Kong X  Hu L 《Journal of genetics》2004,83(1):35-38
Non-syndromic X-linked deafness is a rare form of genetic deafness in humans accounting for a small proportion of all hereditary hearing loss. Different clinical forms of non-syndromic X-linked deafness have been described, and most of these have been mapped. Here, we report a Chinese family affected by a congenital profound sensorineural hearing loss. All phenotypes of this family are clinically compatible with non-syndromic sensorineural deafness (DFN2). A maximum two-point Lod score of 2.32 was obtained at markerDXS6797 (θ = 0.00). Recombinants define a region of 4.3 cm flanked by markersDXS6799 andGATA172D05. This region overlaps the previously reported DFN2 region by 2.0 cm.  相似文献   

3.
The X-linked recessive type of retinitis pigmentosa (XLRP) causes progressive night blindness, visual field constriction, and eventual blindness in affected males by the third or fourth decade of life. The biochemical basis of the disease is unknown, and prenatal diagnosis and definitive carrier diagnosis remain elusive. Heterogeneity in XLRP has been suggested by linkage studies of families affected with XLRP and by phenotypic differences observed in female carriers. Localization of XLRP near Xp11.3 has been suggested by close linkage to an RFLP at the locus DXS7 (Xp11.3) detected by probe L1.28. In other studies a locus for XLRP with metallic sheen has been linked to the ornithine transcarbamylase (OTC) locus mapping to the Xp21 region. In this study, by linkage analysis using seven RFLP markers between Xp21 and Xcen, we examined four families with multiple affected individuals. Close linkage was found between XLRP and polymorphic sites OTC (theta = .06 with lod 5.69), DXS84 (theta = .05 with lod 4.08), and DXS206 (theta = .06 with lod 2.56), defined by probes OTC, 754, and XJ, respectively. The close linkage of OTC, 754, and XJ to XLRP localizes the XLRP locus to the Xp21 region. Data from recombinations in three of four families place the locus above L1.28 and below the Duchenne muscular dystrophy (DMD) gene, consistent with an Xp21 localization. In one family, however, one affected male revealed a crossover between XLRP and all DNA markers, except for the more distal DXS28 (C7), while his brother is recombined for this marker (C7) and not other, more proximal markers. This suggests that in this family the XLRP mutation maps near DXS28 and above the DMD locus.  相似文献   

4.
Various polymorphic markers with a random distribution along the X chromosome were used in a linkage analysis performed on a family with apparently Xlinked recessive inheritance of neural tube defects (NTD). The lod score values were used to generate an exclusion map of the X chromosome; this showed that the responsible gene was probably not located in the middle part of Xp or in the distal region of Xq. A further refining of these results was achieved by haplotype analysis, which indicated that the gene for X-linked NTD was located either within Xp21.1-pter, distal from the DMD locus, or in the region Xq12–q24 between DXS106 and DXS424. Multipoint linkage analysis revealed that the likelihood for gene location is highest for the region on Xp. The region Xq26–q28, which has syntenic homology with the segment of the murine X chromosome carrying the locus for bent tail (Bn), a mouse model for X-linked NTD, is excluded as the location for the gene underlying X-linked NTD in the present family. Thus, the human homologue of the Bn gene and the present defective gene are not identical, suggesting that more than one gene on the X chromosome plays a role in the development of the neural tube.  相似文献   

5.
Multipoint linkage analysis in Menkes disease.   总被引:1,自引:0,他引:1       下载免费PDF全文
Linkage analyses were performed in 11 families with X-linked Menkes disease. In each family more than one affected patient had been diagnosed. Forty informative meioses were tested using 11 polymorphic DNA markers. From two-point linkage analyses high lod scores are seen for DXS146 (pTAK-8; maximal lod score 3.16 at recombination fraction [theta] = .0), for DXS1 (p-8; maximal lod score 3.44 at theta = .0), for PGK1 (maximal lod score 2.48 at theta = .0), and for DXS3 (p19-2; maximal lod score 2.90 at theta = .0). This indicates linkage to the pericentromeric region. Multilocus linkage analyses of the same data revealed a peak for the location score between DXS146(pTAK-8) and DXYS1X(pDP34). The most likely location is between DXS159 (cpX289) and DXYS1X(pDP34). Odds for this location relative to the second-best-supported region, between DXS146(pTAK-8) and DXS159 (cpX289), are better than 74:1. Visualization of individual recombinant X chromosomes in two of the Menkes families showed the Menkes locus to be situated between DXS159(cpX289) and DXS94(pXG-12). Combination of the present results with the reported absence of Menkes symptoms in male patients with deletions in Xq21 leads to the conclusion that the Menkes locus is proximal to DXSY1X(pDP34) and located in the region Xq12 to Xq13.3.  相似文献   

6.
Linkage analysis is described in a family with X-linked mental retardation, ataxia, weakness, floppiness, delayed motor development, absence of deep tendon reflexes, hearing impairment and loss of vision (MIM no. 301835). The disease has a fatal course due to the susceptibility of the patients to infections, especially of the respiratory tract. Clinical signs indicate impairment of the posterior columns, peripheral motor and sensory neurons and the second and eighth cranial nerves and/or their nuclei. The involvement of the posterior columns of the spinal cord is further suggested by the almost complete absence of myelinated fibers therein. We localized the responsible gene(s) to Xq21.33–q24 between DXS1231 and DXS1001 with a maximum lod score of 6.97. The proteolipid protein gene, which codes for two myelin proteins of the central nervous system and is located in this region, was considered as a candidate gene for this disorder. However, no mutations were found in the protein-coding part of this gene. Received: 22 March 1996  相似文献   

7.
The DMD gene, which spans more than 2,000 kbp, has been assigned to band Xp21 of the X chromosome. Two subclones (PERT 87-1 and PERT 87-15) of the intragenic locus DXS164 physically are separated by approximately 60 kbp. Linkage studies were done in 49 informative DMD families by using the LINKAGE program. Crossing-over between the loci studied occurred in four families. A recombination rate of 4% (support interval [Zmax-1] 1%-10%), which was 54 (support interval 14-135-fold) times higher than expected, was found with a maximum lod score of 13.50. These data suggest a hot spot for recombination within DXS164.  相似文献   

8.
Nance-Horan Syndrome (NHS) or X-linked cataract-dental syndrome (MIM 302350) is a disease of unknown pathogenesis characterized by congenital cataracts and dental anomalies. We performed linkage analysis in three kindreds with NHS by using six RFLP markers between Xp11.3 and Xp22.3. Close linkage was found between NHS and polymorphic loci DXS43 (theta = 0 with lod score 2.89), DXS41 (theta = 0 with lod score 3.44), and DXS67 (theta = 0 with lod score 2.74), defined by probes pD2, p99-6, and pB24, respectively. Recombinations were found with the marker loci DXS84 (theta = .04 with lod score 4.13), DXS143 (theta = .06 with lod score 3.11) and DXS7 (theta = .09 with lod score 1.68). Multipoint linkage analysis determined the NHS locus to be linked completely to DXS41 (lod score = 7.07). Our linkage results, combined with analysis of Xp interstitial deletions, suggest that the NHS locus is located within or close to the Xp22.1-Xp22.2 region.  相似文献   

9.
Autosomal dominant nonsyndromic hearing loss (ADNSHL) accounts for about one-fifth of hereditary hearing loss in humans. In the present study, we have analyzed a three-generation family with 14 of its members manifesting ADNSHL, using a genome-wide linkage mapping approach. We found a novel locus DFNA59 between the D11S929 and D11S480 markers in the chromosome location 11p14.2–q12.3. The highest two-point lod score of 5.72 at recombination fraction = 0 was obtained for D11S4152, D11S4154, D11S1301, D11S905 and D11S1344. The critical genomic region comprising about 37 megabases of DNA is proposed to carry a gene for ADNSHL in the family. About 50 cochlear-expressed genes mapping to the region are strong candidates which we propose to examine to identify the gene responsible for the hearing impairment. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.  相似文献   

10.
The AMELX gene located at Xp22.1-p22.3 encodes for the enamel protein amelogenin and has been implicated as the gene responsible for the inherited dental abnormality X-linked amelogenesis imperfecta (XAI). Three families with XAI have been investigated using polymorphic DNA markers flanking the position of AMELX. Using two-point linkage analysis, linkage was established between XAI and several of these markers in two families, with a combined lod score of 6.05 for DXS16 at theta = 0.04. This supports the involvement of AMELX, located close to DXS16, in the XAI disease process (AIH1) in those families. Using multipoint linkage analysis, the combined maximum lod score for these two families was 7.30 for a location of AIH1 at 2 cM distal to DXS16. The support interval around this location extended about 8 cM proximal to DXS92, and the AIH1 location could not be precisely defined by multipoint mapping. Study of recombination events indicated that AIH1 lies in the interval between DXS143 and DXS85. There was significant evidence against linkage to this region in the third family, indicating locus heterogeneity in XAI. Further analysis with markers on the long arm of the X chromosome showed evidence of linkage to DXS144E and F9 with no recombination with either of these markers. Two-point analysis gave a peak lod score at DXS144E with a maximum lod score of 2.83 at theta = 0, with a peak lod score in multipoint linkage analysis of 2.84 at theta = 0. The support interval extended 9 cM proximal to DXS144E and 14 cM distal to F9.(ABSTRACT TRUNCATED AT 250 WORDS)  相似文献   

11.
X-linked cardioskeletal myopathy with neutropenia and abnormal mitochondria is clinically characterized by congenital dilated cardiomyopathy, skeletal myopathy, recurrent bacterial infections, and growth retardation. We analyzed linkage between the disease locus and X-chromosomal markers in a family with seven carriers, four patients, and eight unaffected sons of carriers. Highest lod scores obtained by two-point linkage analysis were 2.70 for St14.1 (DXS52, TaqI) at a recombination fraction of zero and 2.53 for cpX67 (DXS134) at a recombination fraction of zero. Multipoint linkage analysis resulted in a maximum lod score of 5.24 at the position of St35.691 (DXS305). The most distal recombination detected in this family was located between the markers II-10 (DXS466) and DX13 (DXS15). These data indicate the location of the mutated gene at Xq28.  相似文献   

12.
DNA linkage analysis of X-linked retinoschisis   总被引:10,自引:2,他引:8  
Summary Four families with juvenile retionoschisis (RS) have been studied by linkage analysis utilizing eleven polymorphic X-chromosomal markers. The results suggest a close linkage between DXS43, DXS41, and DXS208 and the RS locus at Xp22. The RS locus is distal to the OTC locus, DXS84, and the DMD locus but proximal to DXS85. No recombination events were observed between the RS locus and DXS43 and DXS41. The maximum likelihood estimate of the recombination fraction () was thus zero and the peak lod scores () were 4.98 (DXS43) and 4.09 (DXS41). The linkage data suggest that the gene order on Xp is DXS85-(DXS43, RS, DXS41)-DMD-DXS84-OTC.  相似文献   

13.
The gene responsible for X-linked cleft palate and ankyloglossia (CPX) has previously been localized to the proximal region of the q arm of the X chromosome in both Icelandic and North American Indian kindreds. In this study, further linkage analysis has been performed on the Icelandic family and has resulted in a significant reduction in the size of the interval containing the mutated gene. A new polymorphism at DXS95, together with DXS1002 and DXS349, defines the proximal boundary of the CPX interval, whereas DXYS1X defines the distal boundary. Multipoint analysis supports this localisation with a peak lod score of 12.7, more than 2 lod score units higher than the next most likely position. In order to assess the physical size of the CPX interval prior to initiating yeast artificial chromosome cloning, metaphase fluorescence in situ hybridisation analysis was performed with the closest flanking markers. The size of the interval between DXS95 and DXYS1X was estimated to be approximately 2–3 Mb.  相似文献   

14.
Summary Three families with androgen resistance syndromes — two with testicular feminization and one with Reifenstein syndrome — have been studied for linkage analysis. Using three cloned DNA sequences from the centromere region and the proximal long arm of the X chromosome (p8, pDP34, and S9, which define respectively the chromosomal segments DXS1, DXYS1, and DXS17), we found no recombination between the DXS1 locus and the mutant genes in the three families. Assuming that these disorders are the result of allelic mutations at the same locus for the androgen receptor, we can conclude that there is a close linkage between DXS1 and the androgen receptor locus, with a maximum lod score =3.5 at a recombination fraction =0.0 using the LIPED program (Ott 1974).  相似文献   

15.
A locus (CPX) responsible for X-linked cleft palate and ankyloglossia was previously mapped to the proximal long arm of the X chromosome through DNA marker linkage studies in two large kindreds: an Icelandic family and a British Columbia (B.C.) Native family. In this study, additional linkage analyses have been performed in the B.C. family and in a newly identified Manitoba Mennonite family with X-linked cleft palate and ankyloglossia. The Manitoba CPX locus maps to the same region as Icelandic and B.C. CPX. Two-point disease-tomarker linkage analyses in the Manitoba family indicate a maximum lod score (Zmax) between CPX and DXS349 (Zmax=3.33 at ). In multipoint linkage analysis, combined data from the B.C. and Manitoba families suggest that the most likely location for CPX is at DXS447 in Xq21.1 (multipoint Z=13.5). The support interval for CPX at DXS447 extends approximately from PGK1 to DXYS1 and includes a newly isolated polymorphic locus DXS1109.  相似文献   

16.
X-linked Amelogenesis imperfecta (AI) is a genetic disorder affecting the formation of enamel. In the present study two families, one with X-linked dominant and one with X-linked recessive AI, were studied by linkage analysis. Eleven cloned RFLP markers of known regional location were used. Evidence was obtained for linkage between the AI locus and the marker p782, defining the locus DXS85 at Xp22, by using two-point analysis. No recombination was scored between these two loci in 15 informative meioses, and a peak lod score (Zmax) of 4.45 was calculated at zero recombination fraction. Recombination was observed between the more distal locus DXS89 and AI, giving a peak lod score of 3.41 at a recombination fraction of .09. Recombination was also observed between the AI locus and the more proximal loci DXS43 and DXS41 (Zmax = 0.09 at theta max = 0.31 and Zmax = 0.61 at theta max = 0.28, respectively). Absence of linkage was observed between the AI locus and seven other loci, located proximal to DXS41 or on the long arm of the X chromosome. On the basis of two-point linkage analysis and analysis of crossover events, we propose the following order of loci at Xp22: DXS89-(AI, DXS85)-DXS43-DXS41-Xcen.  相似文献   

17.
Linkage mapping of a severe X-linked mental retardation syndrome.   总被引:4,自引:2,他引:2       下载免费PDF全文
A four-generation Swedish family with a new type of X-linked mental retardation syndrome was recently reported by Gustavson et al. The complex syndrome includes microcephaly, severe mental retardation, optical atrophy with decreased vision or blindness, severe hearing defect, characteristic facial features, spasticity, seizures, and restricted joint motility. The patients die during infancy or early in childhood. Twenty-one family members, including two affected males, were available for study. Linkage analysis was conducted in the family by using 11 RFLP markers and 10 VNTR markers spread along the X chromosome. A hypervariable short tandem repeat of DXS294 at Xq26 showed a peak two-point lod score of 3.35 at zero recombination fraction. Calculations using the same markers revealed a multipoint peak lod score of 3.65 at DXS294. Crossover events with the centromeric marker DXS424 and the telomeric marker DXS297 delimit a probable region for the gene localization. It is noteworthy that hte disease loci of two other syndromes with overlapping clinical manifestations recently were shown by Turner et al. and Pettigrew et al. to be linked to markers at Xq26.  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.
Summary Linkage data for familial incontinentia pigmenti (IP2) and nine X chromosomal markers are reported. Previously found linkage between IP2 and the DXS52 locus is confirmed with the maximum lod score of 6.19 at a recombination fraction of 0.03. Linkage is also established with loci DXS134, DXS15 and DXS33. Multipoint analysis allows us to localize the IP2 locus outside a block of seven linked markers of the Xq28 region.  相似文献   

20.
Retinitis pigmentosa is the name given to a heterogeneous group of hereditary retinal degenerations characterized by progressive visual field loss, pigmentary changes of the retina, abnormal electroretinograms, and, frequently, night blindness. In this study, we investigated a family with dominant cone-rod degeneration, a variant form of retinitis pigmentosa. We used microsatellite markers to test for linkage to the disease locus and excluded all mapped autosomal loci. However, a marker from the short arm of the X chromosome, DXS989, showed 0% recombination to the disease locus, with a maximum lod (log-odds) score of 3.3. On the basis of this marker, the odds favoring X-linked dominant versus autosomal dominant inheritance are > 10(5):1. Haplotype analysis using an additional nine microsatellite markers places the disease locus in the Xp22.13-p22.11 region and excludes other X-linked disease loci causing retinal degeneration. The clinical expression of the retinal degeneration is consistent with X-linked dominant inheritance with milder, variable effects of Lyonization affecting expression in females. On the basis of these data we propose that this family has a novel form of dominant, X-linked cone-rod degeneration with the gene symbol "RP15."  相似文献   

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