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1.
Segregation distortion of the CTG repeats at the myotonic dystrophy locus. 总被引:3,自引:0,他引:3
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R. Chakraborty D. N. Stivers R. Deka L. M. Yu M. D. Shriver R. E. Ferrell 《American journal of human genetics》1996,59(1):109-118
Myotonic dystrophy (DM), an autosomal dominant neuromuscular disease, is caused by a CTG-repeat expansion, with affected individuals having > or = 50 repeats of this trinucleotide, at the DMPK locus of human chromosome 19q13.3. Severely affected individuals die early in life; the milder form of this disease reduces reproductive ability. Alleles in the normal range of CTG repeats are not as unstable as the (CTG)(> or = 50) alleles. In the DM families, anticipation and parental bias of allelic expansions have been noted. However, data on mechanism of maintenance of DM in populations are conflicting. We present a maximum-likelihood model for examining segregation distortion of CTG-repeat alleles in normal families. Analyzing 726 meiotic events in 95 nuclear families from the CEPH panel pedigrees, we find evidence of preferential transmission of larger alleles (of size < or = 29 repeats) from females (the probability of transmission of larger alleles is .565 +/- 0.03, different from .5 at P approximately equal .028). There is no evidence of segregation distortion during male meiosis. We propose a hypothesis that preferential transmission of larger CTG-repeat alleles during female meiosis can compensate for mutational contraction of repeats within the normal allelic size range, and reduced viability and fertility of affected individuals. Thus, the pool of premutant alleles at the DM locus can be maintained in populations, which can subsequently mutate to the full mutation status to give rise to DM. 相似文献
2.
3.
Anna Cobo Daniel Grinberg Susana Balcells Lluïsa Vilageliu Roser Gonzàlez-Duarte Montserrat Baiget 《Human genetics》1992,89(3):287-291
Summary We used the following polymorphic markers: APOC2 (BanI, BglI, TaqI), CKMM (NcoI, TaqI), and D19S63 (PstI) to haplotype 33 Spanish myotonic dystrophy (DM) families. We analysed the allele and haplotype frequencies of our sample, and the possible association of alleles or haplotypes with the disease. We found a slight linkage disequilibrium between APOC2 (BanI) and DM, but no disequilibrium when using all other APOC2 and CKMM RFLPs; this agrees with data previously reported. In addition, we found a very strong linkage disequilibrium when using D19S63 (PstI), the + allele being associated with the DM locus. This disequilibrium in the Spanish population indicates that D19S63 is very close to the DM locus. 相似文献
4.
A method to measure the germline mutations induced by cancer treatment in humans is needed. To establish such a method we used a transgenic mouse model consisting of a human DNA repeat locus that has a high spontaneous mutation frequency as a biomarker. Alterations in repeat number were measured in individual sperm from mice hemizygous for an expanded (CTG)(162) human myotonic dystrophy type 1 (DM1) microsatellite repeat using single genome-equivalent (g.e.) PCR and detection by a DNA fragment analyzer. Mutation frequencies were measured in DNA from sperm from controls and sperm derived from stem spermatogonia, differentiating spermatogonia, and spermatocytes exposed to radiation and from spermatocytes of mice treated with cyclophosphamide. There was no increase above control levels in mutations, scored as >1 repeat changes, in any of the treated groups. However, moderately large deletion mutants (between 9 and 20 repeat changes) were observed at frequencies of 2.2% when spermatocytes were treated with cyclophosphamide and, 1.8 and 2.5% when spermatocytes and stem cells, respectively, were treated with radiation, which were significantly higher than the frequency of 0.3% in controls. Thus, radiation and cyclophosphamide induced deletions in the expanded DM1 trinucleotide repeat. PCR artifacts were characterized in sperm DNA from controls and from mice treated with radiation; all artifacts involved losses of more than 20 DM1 repeats, and surprisingly the artifact frequency was higher in treated sperm than in control sperm. The radiation-induced increase in the frequency of PCR artifacts might reflect alterations in sperm DNA that destabilize the genome not only during PCR amplification but also during early embryonic development. 相似文献
5.
A reordering of human chromosome 19 long-arm DNA markers and identification of markers flanking the myotonic dystrophy locus 总被引:9,自引:0,他引:9
The gene for myotonic dystrophy (DM), the most common form of adult muscular dystrophy, has previously been mapped to the proximal long arm of chromosome 19. We have conducted linkage analysis on 53 DM families (comprising 421 individuals) using seven DM-linked DNA markers. This analysis, combined with our somatic cell hybrid mapping panel data, places the DM locus more distal on the chromosome 19 long arm than previously thought. Further, we have been able to unequivocally identify DNA markers that flank the disease locus. The definition of a 10-cM region of chromosome 19 that contains the DM locus should prove useful in both the search for the causative gene and the molecular diagnosis of DM. 相似文献
6.
Triplet repeat expansion in 3 untranslated region of myotonic dystrophy protein kinase (DMPK) gene has been implicated as causative in myotonic dystrophy (DM). In cases of DM, high levels of somatic instability have been reported, in which inter-tissue repeat length differences as large as 3000 repeats have been observed. This study highlights the inter-tissue (CTG)n expansion variability at the DMPK locus. Molecular analysis of DMPK gene, encompassing the triplet repeat expansion, was carried out in 31 individuals (11 clinically identified DM patients, 20 controls). All controls showed a 2.1kb band (upto 35 CTG repeats), while four cases exhibited an expansion (>50 repeats). A novel observation was made in one case, wherein the DNA from lymphocytes showed a normal 2.1kb band while the muscle tissue DNA from the same patient was heterozygous for normal and 4.3 kb band (>700 repeats). Our results suggested that because inter-tissue variability existed in the (CTG)n repeat number at DMPK locus, an attempt should be made to evaluate affected tissue along with blood wherever possible prior to making a final diagnosis. This is important not only for diagnosis and prenatal analysis, but also while providing genetic counseling to families. 相似文献
7.
G Jansen P J de Jong C Amemiya C Aslanidis D J Shaw H G Harley J D Brook R Fenwick R G Korneluk C Tsilfidis 《Genomics》1992,13(3):509-517
The mutation involved in myotonic dystrophy (DM) has been mapped to the region between the ERCC1 DNA repair gene and the anonymous D19S51 locus on 19q13.3. Starting at locus D19S112 (probe pX75b), which served as a novel entry site for this chromosome region, we have established a cosmid contig of approximately 200 kb. In the contig, a gene expressed in the brain and a highly informative, 12-allele (TG)n variable simple sequence motif (VSSM) were identified. With this marker, designated X75b-VSSM, a highly characteristic size distribution of alleles linked with DM, which differed significantly from that on normal chromosomes, was observed. Combining our physical mapping and genetic data, we show that the X75b-VSSM marker is the closest distal to DM, thus excluding the DM mutation from the entire telomeric portion of the ERCC1-D19S51 region. 相似文献
8.
F. L. Munier A. L. Murphree L. Arabian P. Flodman M. A. Spence G. Pescia H. P. Rutz 《Human genetics》1994,94(5):484-490
In a previous genotypic study of eight families, we discribed paternal segregation distortion favoring the transmission of mutant alleles at the retinoblastoma gene locus (RB1). In the current study, we reviewed all published retinoblastoma pedigrees with defined ascertainment (n = 150), to determine whether the phenotypic segregation frequency at the RB1 locus is in general influenced by the sex of the transmitting parent. Segregation analysis under complete ascertainment revealed that 49.1% of the offspring of male transmitters were affected, while 44.3% of the offspring of female transmitters were affected. While this difference is not statistically significant, it is consistent with the previous findings. No significant sex distortion could be detected among the progeny of carrier fathers and mothers. In order to quantify the transmission ratio more precisely further prospective molecular genetic analysis is warranted. We propose a biological mechanism to account for a putative segregation distortion, namely that genetic recombination creates clones of spermatogonia that are homozygous for the mutant RB1 allele leading to a non-Mendelian ratio of sperm. This model can be experimentally tested using amplification of DNA from single sperm cells. 相似文献
9.
We compare the evolutionary pressures that direct the modification of gene conversion and meiotic drive at loci subject to purifying and overdominant viability selection. Gene conversion differs from meiotic drive in that modifers do not affect their own segregation ratios, even when linked to the viability locus. Segregation distortion generates gametic level disequilibria between alleles at the viability locus and modifiers of gene conversion and meiotic drive: enhancers of segregation distortion become positively associated with driven alleles. Suppression of gene conversion evolves if the driven allele is marginally disadvantageous (overdominant viability selection), and higher rates evolve if the driven alleles are relatively advantageous (purifying viability selection). Gametic disequilibria permit enhancers of meiotic drive that are linked to the driven locus to promote their own segregation. We attribute the failure of genetic modifiers of gene conversion and meiotic drive to maximinize mean fitness to the generation of such associations. 相似文献
10.
Detection of linkage disequilibrium between the myotonic dystrophy locus and a new polymorphic DNA marker. 总被引:15,自引:10,他引:5
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H G Harley J D Brook J Floyd S A Rundle S Crow K V Walsh M C Thibault P S Harper D J Shaw 《American journal of human genetics》1991,49(1):68-75
We have examined the linkage of two new polymorphic DNA markers (D19S62 and D19S63) and a previously unreported polymorphism with an existing DNA marker (ERCC1) to the myotonic dystrophy (DM) locus. In addition, we have used pulsed-field gel electrophoresis to obtain a fine-structure map of this region. The detection of linkage disequilibrium between DM and one of these markers (D19S63) is the first demonstration of this phenomenon in a heterogeneous DM population. The results suggest that at least 58% of DM patients in the British population, as well as those in a French-Canadian subpopulation, are descended from the same ancestral DM mutation. We discuss the implications of this finding in terms of strategies for cloning the DM gene, for a possible role in modification of risk for prenatal and presymptomatic testing, and we speculate on the origin and number of existing mutations which may result in a DM phenotype. 相似文献
11.
J. J. Magaña P. Cortés-Reynosa R. Escobar-Cedillo R. Gómez N. Leyva-García B. Cisneros 《Molecular biology reports》2011,38(2):1341-1346
Myotonic dystrophy type 1 (DM1), the most common form of adult muscular dystrophy, is caused by anormal expansion of CTG trinucleotide
repeats located in the 3′-untranslated region of the DMPK gene. The clinical features of DM1 are multisystemic and highly
variable, and the unstable nature of CTG expansion causes wide genotypic and phenotypic presentations. In this study, we described
to our knowledge for the first time the molecular diagnosis of myotonic dystrophy type 1 patients in the Mexican population,
applying a fluorescent PCR method in combination with capillary electrophoresis analysis of the amplified products. We identified
expanded alleles in 45 out of 50 patients (90%) with clinical features of myotonic disease. Furthermore, genotyping of 400
healthy subjects revealed the presence of 25 different alleles, ranging in size from 5 to 34 repeats. The most frequent allele
was 13 CTG repeats (38.87%) and the frequency for alleles over 18 CTG repeats was 6.7%. Molecular test is essential for DM1
diagnosis and distribution of the CTG repeat alleles present in the Mexican population are significantly different from those
of other populations. 相似文献
12.
Meiotic segregation analysis of RB1 alleles in retinoblastoma pedigrees by use of single-sperm typing
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Girardet A McPeek MS Leeflang EP Munier F Arnheim N Claustres M Pellestor F 《American journal of human genetics》2000,66(1):167-175
In hereditary retinoblastoma, different epidemiological studies have indicated a preferential paternal transmission of mutant retinoblastoma alleles to offspring, suggesting the occurrence of a meiotic drive. To investigate this mechanism, we analyzed sperm samples from six individuals from five unrelated families affected with hereditary retinoblastoma. Single-sperm typing techniques were performed for each sample by study of two informative short tandem repeats located either in or close to the retinoblastoma gene (RB1). The segregation probability of mutant RB1 alleles in sperm samples was assessed by use of the SPERMSEG program, which includes experimental parameters, recombination fractions between the markers, and segregation parameters. A total of 2,952 single sperm from the six donors were analyzed. We detected a significant segregation distortion in the data as a whole (P=.0099) and a significant heterogeneity in the segregation rate across donors (.0092). Further analysis shows that this result can be explained by segregation distortion in favor of the normal allele in one donor only and that it does not provide evidence of a significant segregation distortion in the other donors. The segregation distortion favoring the mutant RB1 allele does not seem to occur during spermatogenesis, and, thus, meiotic drive may result either from various mechanisms, including a fertilization advantage or a better mobility in sperm bearing a mutant RB1 gene, or from the existence of a defectively imprinted gene located on the human X chromosome. 相似文献
13.
Mutagenic stress modulates the dynamics of CTG repeat instability associated with myotonic dystrophy type 1 总被引:2,自引:1,他引:1
Piñeiro E Fernàndez-López L Gamez J Marcos R Surrallés J Velázquez A 《Nucleic acids research》2003,31(23):6733-6740
The molecular basis of the myotonic dystrophy type 1 is the expansion of a CTG repeat at the DMPK locus. The expanded disease-associated repeats are unstable in both somatic and germ lines, with a high tendency towards expansion. The rate of expansion is directly related to the size of the pathogenic allele, increasing the size heterogeneity with age. It has also been suggested that additional factors, including as yet unidentified environmental factors, might affect the instability of the expanded CTG repeats to account for the observed CTG size dynamics over time. To investigate the effect of environmental factors in the CTG repeat instability, three lymphoblastoid cell lines were established from two myotonic dystrophy patients and one healthy individual, and parallel cultures were concurrently expanded in the presence or absence of the mutagenic chemical mitomycin C for a total of 12 population doublings. The new alleles arising along the passages were analysed by radioactive small pool PCR and sequencing gels. An expansion bias of the stepwise mutation was observed in a (CTG)124 allele of a cell line harbouring two modal alleles of 28 and 124 CTG repeats. Interestingly, this expansion bias was clearly enhanced in the presence of mitomycin C. The effect of mitomycin C was also evident in the normal size alleles in two cell lines with alleles of 13/13 and 12/69 repeats, where treated cultures showed new longer alleles. In conclusion, our results indicate that mitomycin C modulates the dynamics of myotonic dystrophy-associated CTG repeats in LBCLs, enhancing the expansion bias of long-pathogenic repeats and promoting the expansion of normal length repeats. 相似文献
14.
Linkage relationships of the protein kinase C gamma gene which exclude it as a candidate for myotonic dystrophy 总被引:2,自引:0,他引:2
K J Johnson P J Jones N Spurr E Nimmo J Davies H Creed M Weiss R Williamson 《Cytogenetics and cell genetics》1988,48(1):13-15
Using a cDNA probe for the gamma gene of protein kinase C (PKCG), an informative RFLP with a PIC value of 0.62 has been identified with the enzyme MspI. The polymorphic bands have been assigned to chromosome 19. Analysis of the segregation of alleles for this probe in myotonic dystrophy families show several recombinants between PKCG and myotonic dystrophy (DM) and exclude this gene as a candidate for DM. Linkage relationships between PKCG and other loci on chromosome 19 are presented which exclude PKCG from the proximal region of chromosome 19 and which are consistent with the localization being at 19q13.2----qter. 相似文献
15.
One of the world highest prevalence estimates of myotonic dystrophy (DM) has been reported in the Croatian region Istria. To analyse the population genetic characteristics of DM locus in Istria, two intragenic and three extragenic polymorphic markers were tested. The Southern blot technique was used for D19S63 locus analysis, whereas PCR analysis was performed for CKMM, Alu polymorphism, DMPK (G/T) intron 9/HinfI polymorphism, and D19S207 genetic markers. The compound haplotypes segregating with DM were established. A complete association between the DM mutation and D19S63, D19S207, intron 9/HinfI polymorphism and Alu polymorphism markers were found. In all DM chromosomes: D19S63 and Alu markers had the allele 1 in common; D19S207 had the allele 3 in common, DMPK (G/T) intron 9/HinfI marker had the allele 2 in common. The analysis of CKMM polymorphism revealed genotype heterogeneity; in DM chromosomes either allele 2 or allele 4 were found. The haplotype analysis in the population of Croatian Istria supports the linkage disequilibrium between the DM mutation and Alu polymorphism, intron 9/HinfI polymorphism, D19S63 and D19S207 markers as reported worldwide. The results of the haplotype analysis suggest a common origin of the mutation in Istrian population. 相似文献
16.
Somatic heterogeneity of the CTG repeat in myotonic dystrophy is age and size dependent. 总被引:22,自引:1,他引:21
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L J Wong T Ashizawa D G Monckton C T Caskey C S Richards 《American journal of human genetics》1995,56(1):114-122
The most common form of adult muscular dystrophy, myotonic dystrophy (DM), is caused by the abnormal expansion of the CTG repeat, located in the 3' UTR of the DM gene. The expanded-CTG allele often presents as a diffused band on Southern blot analysis, suggesting somatic mosaicism. In order to study the somatic instability of the CTG repeat, we have investigated the dynamics of the size heterogeneity of the CTG expansion. Size heterogeneity is shown as a smear on Southern blot and is measured by the midpeak-width ratio of the expanded allele to the normal sized allele. The ratio is also corrected for compression in the higher-molecular-weight region. It is found that the size heterogeneity of the expanded-CTG repeats, of 173 DM patients, correlates well with the age of the patient (r = .81, P << .001). The older patients show larger size variation. This correlation is independent of the sex of either the patient or the transmitting parent. The size heterogeneity of the expansion, based on age groups, is also dependent on the size of the expanded trinucleotide repeat. However, obvious size heterogeneity is not observed in congenital cases, regardless of the size of expansion. Comparison of individual patient samples collected at two different times has confirmed that the degree of size heterogeneity increases with age and has revealed a subtle but definite upward shift in the size of the expanded-CTG allele. The progression of the CTG repeat toward larger expansion with age is further confirmed by small-pool PCR assay that resolved the heterogeneous fragments into discrete bands.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
17.
D. J. Shaw A. L. Meredith J. D. Brook M. Sarfarazi H. G. Harley S. M. Huson G. I. Bell P. S. Harper 《Human genetics》1986,74(3):267-269
Summary Myotonic dystrophy is associated with disturbances in the insulin response, possibly due to an abnormality of the insulin receptor. Both the myotonic dystrophy (DM) and insulin receptor (INSR) genes are on chromosome 19. Using a cloned gene probe for INSR, we have studied its linkage relationships with the DM locus and other chromosome 19 markers. The results show that INSR is not closely linked to DM, but is located very close to C3, in the region 19pter-19p13.2. This implies that the basic genetic defect which causes DM is not directly responsible for the disturbed insulin response in these patients. 相似文献
18.
M. Gennarelli M. Pavoni F. Cruciani G. De Stefano B. Dallapiccola G. Novelli 《Human genetics》1999,105(1-2):165-167
Myotonic dystrophy (DM) is a dominantly inherited neuromuscular disease, highly variable and multisystemic, which is caused
by the expansion of a CTG repeat located in the 3′ untranslated region of the DMPK gene. Normal alleles show a copy number
of 5–37 repeats on normal chromosomes, amplified to 50–3000 copies on DM chromosomes. The trinucleotide repeat shows a trimodal
allele distribution in the majority of the examined population. The first class includes alleles carrying (CTG)5, the second class, alleles in the range 7–18 repeats, and the third class, alleles (CTG)≥
19. The frequency of this third class is directly related to the prevalence of DM in different populations, suggesting that
normal large-sized alleles predispose toward DM. We studied CTG repeat allele distribution and Alu insertion and/or deletion polymorphism at the myotonic dystrophy locus in two major Ethiopian populations, the Amhara and
Oromo. CTG allele distribution and haplotype analysis on a total of 224 normal chromosomes showed significant differences
between the two ethnic groups. These differences have a bearing on the out-of-Africa hypothesis for the origin of the DM mutation.
In addition, (CTG)≥
19 alleles were exclusively detected in the Amhara population, confirming the predisposing role of these alleles compared with
the DM expansion-mutation.
Electronic Publication 相似文献
19.
Jules Hernández-Sánchez Dave Waddington Pamela Wiener Chris S. Haley John L. Williams 《Mammalian genome》2002,13(3):164-168
A genome-wide search for markers associated with BSE incidence was performed by using Transmission-Disequilibrium Tests (TDTs).
Significant segregation distortion, i.e., unequal transmission probabilities of alleles within a locus, was found for three
marker loci on Chromosomes (Chrs) 5, 10, and 20. Although TDTs are robust to false associations owing to hidden population
substructures, it cannot distinguish segregation distortion caused by a true association between a marker and bovine spongiform
encephalopathy (BSE) from a population-wide distortion. An interaction test and a segregation distortion analysis in half-sib
controls were used to disentangle these two alternative hypotheses. None of the markers showed any significant interaction
between allele transmission rates and disease status, and only the marker on Chr 10 showed a significant segregation distortion
in control individuals. Nevertheless, the control group may have been a mixture of resistant and susceptible but unchallenged
individuals. When new genotypes were generated in the vicinity of these three markers, evidence for an association with BSE
was confirmed for the locus on Chr 5.
Subscribers can view a supplementary table for this article at url:http:// link.springer-ny/link/service/journals/OO335/contents/01/3068/paper/
index.html. 相似文献
20.
Founder effect and prevalence of myotonic dystrophy in South Africans: molecular studies. 总被引:3,自引:1,他引:2
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A high prevalence of myotonic dystrophy (DM) has been described in South African Caucasoid Afrikaans-speaking families in the northern Transvaal. Evidence is presented for a strong founder effect, with a single haplotype occurring on 68% of all Caucasoid DM chromosomes; among the Afrikaans speakers, the proportion was 83%. In addition to this major haplotype, five minor DM haplotypes in the Caucasoids and two minor haplotypes in DM individuals of mixed ancestry were found. All DM chromosomes, however, had a common haplotype core, namely, Alu (ins), HinfI-2 (intron 9), and TaqI-2 (D19S463). We have detected significant linkage disequilibrium between the DM mutation and particular alleles of the extragenic markers D19S112 and D19S207. Significant differences were found in allele and haplotype distributions in the Caucasoid DM and non-DM chromosomes and Negroid non-DM chromosomes. These findings together with the strong association of allele 3 at the D19S63 locus on 93% (14/15) of the South African DM chromosomes suggest that the majority of present-day DM mutations in South African Caucasoids may have originated from a common initial founder who introduced one of the European ancestral mutations. 相似文献