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Results for “DNA Sequence, Unstable”

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PubMed1996

Detailed comparative map of human chromosome 19q and related regions of the mouse genome.

One of the larger contiguous blocks of mouse-human genomic homology includes the proximal portion of mouse chromosome 7 and the long arm of human chromosome 19. Previous studies have demonstrated the close relationship between the two regions, but have also indicated significant rearrangements in the relative orders of homologous mouse and human genes. Here we present the genetic locations of the homologs of 42 human chromosome 19q markers in the mouse, with an emphasis on genes also included in the human chromosome 19 physical map. Our results demonstrate that despite an overall inversion of sequences relative to the centromere, apparent "transpositions" of three gene-rich segments, and a local inversion of markers mapping near the 19q telomere, gene content, order, and spacing are remarkably well conserved throughout the lengths of these related mouse and human regions. Although most human 19q markers have remained genetically linked in mouse, one small human segment forms a separate region of homology between human chromosome 19q and mouse chromosome 17. Three of the four rearrangements of mouse versus human 19q sequences involve segments that are located directly adjacent to each other in 19q13.3-q13.4, suggesting either the coincident occurrence of these events or their common association with unstable DNA sequences. These data permit an unusually in-depth examination of this large region of mouse-human genomic homology and provide an important new tool to aid in the mapping of genes and associated phenotypes in both species.

Animals↗

PubMed2003

Tumbling down a different pathway to genetic instability.

Ulcerative colitis (UC), a chronic inflammatory condition associated with a predisposition to colon cancer, is frequently characterized by DNA damage in the form of microsatellite instability (MSI). A new report links inflammation in UC with increases in the DNA repair enzymes 3-methyladenine DNA glycosylase and apurinic/apyrimidinic endonuclease, and, paradoxically, with increased MSI. These findings may represent a novel mechanism contributing to MSI in chronic inflammation.

Base Sequence↗

PubMed2004

Mitochondrial DNA instability in malignant melanoma of the skin is mostly restricted to nodular and metastatic stages.

Ultraviolet (UV) radiation is thought to be a major contributor to the development of sporadic malignant melanoma of the skin. It may induce alterations in genomic or mitochondrial DNA (mtDNA), especially C to T or CC to TT changes. Mutations or other alterations in mtDNA have been reported in a variety of human cancers and may be due to different mechanisms. In this study, we have attempted to elucidate whether aberrations in the mtDNA of melanoma are due to UV radiation or other factors by investigating two parts of the mitochondrial D-loop and two mitochondrial genes, as well as looking for the delta4977 mtDNA deletion and mtDNA duplications, in 61 primary malignant melanomas and neighbouring normal skin tissue (in 70% of primary tumours; otherwise, corresponding blood samples). Point mutations were a rare feature, occurring in only seven tumour samples and never as a C to T change, whereas mtDNA instability in the D-loop (mtMSI) was found in 13% of primary nodular tumours and 20% of metastases. A de novo delta4977 mtDNA deletion was demonstrated in 10% of melanomas; in 20% of patients, mtDNA duplications and/or the delta4977 mtDNA deletion was detectable. Our data indicate that mtDNA alterations in malignant melanoma are not induced by UV radiation. In addition, point mutations and mtMSI were mostly a feature of nodular and metastatic melanoma samples.

Adult↗

PubMed2004

Relationship between mitochondrial DNA instability, mitochondrial DNA large deletions, and nuclear microsatellite instability in head and neck squamous cell carcinomas.

Mitochondrial DNA (mtDNA) mutations in coding and noncoding regions have been reported in a variety of human cancers. Despite a greater number of studies, the relationship between such alterations and nuclear microsatellite instability (nMSI) of the tumor cells remains controversial. To contribute new data to this discussion, we investigated head and neck squamous cell carcinomas (HNSCC) for mutations and mitochondrial microsatellite instability (mtMSI) in 2 parts of the mitochondrial D-loop as well as mutations in 2 mitochondrial genes and for the delta4977 mtDNA deletion. These results were compared with data of an analysis for microsatellite instability at IGFIIR, hMSH3, hMSH6, and 5 dinucleotide repeats. We found mtMSI, low nMSI, and high nMSI in 42%, 36%, and 13% of HNSCC primary tumors, respectively. A de novo delta4977 mtDNA deletion could be demonstrated in 25% of HNSCCs. A correlation between mtMSI and nMSI or between a de novo occurrence of the delta4977 mtDNA deletion and nMSI could not be detected in our HNSCC samples (P values 0.527 and 0.078, respectively). Nevertheless, the high rate of mtMSI suggests an involvement of mtDNA alterations in the tumorigenesis of this head and neck cancer and supports the proposal that this aberration may be a new tumor marker.

Adult↗

PubMedDate not supplied

The DNA-instability test as a specific marker of malignancy and its application to detect cancer clones in borderline malignancy.

Recent progress in cytogenetic and biochemical mutation assay technologies has enabled us to detect single gene alterations and gross chromosomal rearrangements, and it became clear that all cancer cells are genetically unstable. In order to detect the genome-wide instability of cancer cells, a new simple method, the DNA-instability test, was developed. The methods to detect genomic instability so far reported have only demonstrated the presence of qualitative and quantitative alterations in certain specific genomic loci. In contrast to these commonly used methods to reveal the genomic instability at certain specific DNA regions, the newly introduced DNA-instability test revealed the presence of physical DNA-instability in the entire DNA molecule of a cancer cell nucleus as revealed by increased liability to denature upon HCl hydrolysis or formamide exposure. When this test was applied to borderline malignancies, cancer clones were detected in all cases at an early-stage of cancer progression. We proposed a new concept of "procancer" clones to define those cancer clones with "functional atypia" showing positivities for various cancer markers, as well as DNA-instability testing, but showing no remarkable ordinary "morphological atypia" which is commonly used as the basis of histopathological diagnosis of malignancy.

Animals↗

PubMed2006

SnoN expression is differently regulated in microsatellite unstable compared with microsatellite stable colorectal cancers.

BACKGROUND: SnoN is an important regulator of the transforming growth factor beta (TGFbeta) signalling pathway and has been shown to exhibit both tumour promotion and suppression activity. METHODS: To further explore the role of this complex molecule in colorectal tumorigenesis, we examined 52 paired normal and tumour colorectal specimens stratified by level of microsatellite instability; 18 with high-level microsatellite instability (MSI-H) and 34 microsatellite stable (MSS). SnoN transcript expression was quantitated by real-time PCR and analysed with respect to clinical indicators of prognosis. RESULTS: Within the MSI-H subgroup, SnoN was commonly either up-regulated (6/18, 33%) or down-regulated (7/18, 39%). A significantly different distribution of SnoN expression was observed in MSS cancers compared with MSI-H (P < or = 0.001). Whilst 17/34 (50%) of MSS tumours demonstrated up-regulation, none showed down-regulated expression. Within the MSI-H subgroup, up-regulation was significantly correlated with lack of repeat tract mutation in the TGFbetaRII gene (P < or = 0.025), suggesting that SnoN is more frequently up-regulated in the presence of functional TGFbeta signalling. CONCLUSION: Together these data support the notion that SnoN has both oncogenic and tumour suppressive properties depending on other genetic changes within the tumour, and that the MSI-H pathway of colorectal tumorigenesis presents an excellent model for the study of these opposing functions.

Colorectal Neoplasms↗

PubMed1996

Refining a proximal breakpoint cluster at chromosome 3p11.2 in non-papillary renal cell carcinomas.

Our previous cytogenetic and microsatellite analyses showed a terminal deletion of chromosome 3p segments with a breakpoint region between 3p11.2 and 3p14.1 bands in 98% of non-papillary renal cell carcinomas (RCC). This breakpoint region covers approx. 20-25 cM genetic distance. Earlier, we found a higher frequency of rearrangements at chromosome 3p11.2 and have therefore now analyzed 74 sporadic and 26 VHL-associated RCCs with 6 polymorphic microsatellite markers mapped to this region. Thirty-three per cent of the breakpoints were mapped to a genetic distance of less than one-twentieth of the large breakpoint region 3p11.2-14.1. We suggest that unstable DNA sequences at chromosome 3p11.2 serve as a genetic basis for deletions and homologous and non-homologous recombinations to remove distal 3p sequences with one copy of RCC gene(s) in different types of tumors. We have identified a YAC clone 909d5 that spans the most frequently occurring breaks between loci D3S1251, D3S1101, and D3S1552 and allows this region to be cloned.

Carcinoma, Renal Cell↗

PubMed1996

Anticipation of autosomal dominant progressive external ophthalmoplegia with hypogonadism.

A large Swedish family with members affected by progressive external ophthalmoplegia with hypogonadism were followed-up and reviewed. Hypogonadism included delayed sexual maturation, primary amenorrhea, early menopause, and testicular atrophy. Cataracts, cerebellar ataxia, neuropathy, hypoacusia, pes cavus, tremor, parkinsonism, depression, and mental retardation were other features observed in this family. Muscle biopsy samples of advanced cases showed ragged-red fibers, focal cytochrome c oxidase deficiency, and multiple mtDNA deletions by Southern blot analysis. An autosomal dominant mode of inheritance was evident with anticipation in successive generations. Linkage analysis excluded the chromosome 10q23.3-q24.3 region reported as being linked to the disease in a Finnish family with autosomal dominant progressive external ophthalmoplegia. We report for the first time clinical evidence for anticipation in a family with autosomal dominant progressive external ophthalmoplegia. We hypothesize that the nuclear gene causing this enigmatic disorder may be directly influenced by an expansion of an unstable DNA sequence and that the resulting phenotype is caused by a concerted action with multiple deletions of mtDNA.

Adult↗

PubMed2000

Anticipation in bipolar affective disorder: is age at onset a valid criterion?

Anticipation has been suggested among the genetic mechanisms of bipolar disorder (BD), prompting the search for unstable DNA sequences. Past studies of anticipation in BD have generally relied on observed shift in the age at onset between parental and offspring generations. Such a shift, however, may be caused by a number of other factors difficult to correct for. We investigated age at onset distributions in a sample of 161 related subjects and in a sample of "pseudofamilies" consisting of 320 unrelated subjects selected from a large epidemiological cohort using Monte-Carlo simulation to mimic the family sample. Comparison of age at onset distributions in both samples shows a difference between the generations, but of a similar magnitude in each sample. This suggests that age at onset alone may not be a sufficient criterion of anticipation. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:804-807, 2000.

Adult↗

PubMed1994

Haplotype analysis at the FRAXA locus in the Japanese population.

Fragile X syndrome, one of the most common human genetic diseases, is characterized by a unique genetic mechanism which involves dynamic mutation in a heritable unstable DNA sequence, a p(CCG)n repeat, in the FRAXA locus. It has recently been suggested that a few founder chromosomes are responsible for most fragile X mutations in the Caucasian population. In order to investigate the origin of the fragile X mutations in the Japanese population, we analyzed haplotypes of the FRAXA locus in 40 unrelated fragile X chromosomes and 142 normal X chromosomes in Japanese males, by using two polymorphic AC repeats, FRAXAC1 and FRAXAC2, which flank the fragile site. This analysis provided evidence for founder fragile X chromosomes in the Japanese population, similar to that in Caucasians, although different haplotypes are involved. The distribution of normal allele size of the p(CCG)n repeat among the X chromosomes in the Japanese population is very similar to that reported for Caucasians, except that the most frequent copy number (n = 28) is one copy less than that in Caucasians and that there is an additional peak at 35 copies. There is significant correlation between FRAXAC alleles and the p(CCG)n repeat copy number in non-fragile X chromosomes, however, alleles with more than 31 copies of the p(CCG)n repeat do not segregate with either of the fragile X common FRAXAC haplotypes.

Asian People↗

PubMed2007

Common fragile site FRA11G and rare fragile site FRA11B at 11q23.3 encompass distinct genomic regions.

Fragile sites are specific genomic loci that are particularly prone to chromosomal breakage. Based on their incidence in the human population, they are divided into rare fragile sites occurring in less than 5% of all individuals and common fragile sites being a constitutional feature of the genome of probably all individuals. In this study, cloning of unstable DNA sequences, which have been previously genetically tagged with a marker gene, was the basis for defining the genomic localization of the common fragile site FRA11G at 11q23.3. Mapping of the fragile site with six-color fluorescence in situ hybridization (FISH) resulted in the precise genomic localization of FRA11G to a 4.5 Mb region. The chromosomal subband 11q23.3 harbors both the common fragile site FRA11G and the rare fragile site FRA11B. Here, we show that FRA11G maps 0.8 Mb proximal to the genomic region previously defined to be affected by expression of FRA11B; thus, the common and the rare fragile sites at 11q23.3 encompass distinct genomic regions. The region of FRA11G is known to be involved in somatic and germline recurrent aberrations, and it is conceivable that genetic damage resulting from this fragile site might contribute to clinical phenotypes.

Breast Neoplasms↗

PubMed1993

Conflict between feminizing sex ratio distorters and an autosomal masculinizing gene in the terrestrial isopod Armadillidium vulgare Latr.

Female sex determination in the pill bug Armadillidium vulgare is frequently under the control of feminizing parasitic sex factors (PSF). One of these PSF is an intracytoplasmic Wolbachia-like bacterium (F), while the other (f) is suspected of being an F-bacterial DNA sequence unstably integrated into the host genome. In most wild populations harboring PSF, all individuals are genetic males (ZZ), and female phenotypes occur only due to the presence of PSF which overrides the male determinant carried by the Z chromosome (females are thus ZZ +F or ZZ +f neo-females). Here we report the effects of the conflict between these PSF and a dominant autosomal masculinizing gene (M) on phenotypes. The M gene is able to override the feminizing effect of the f sex factor and, consequently, male sex may be restored. However, M is unable to restore male sex when competing with the F bacteria. It seems that the main effect of M is to delay the expression of F bacteria slightly, inducing intersex phenotypes. Most of these intersexes are functional females, able to transmit the masculinizing gene. The frequency of M and its effects on the sex ratio in wild populations are discussed.

Animals↗

PubMed1992

Characterisation of a new rare fragile site easily confused with the fragile X.

A new fragile site (FRAXE) in Xq28 is described. It appears to be a typical folate sensitive fragile site. The fragile site is not associated with mental retardation, it does not give abnormal results when subjected to Southern analysis with probe pfxa3 which detects the unstable DNA sequence characteristic of fragile X syndrome. In situ hybridization mapping locates the fragile site between 150 kb and 600 kb distal to FRAXA. The distinction between the two fragile sites is important clinically since cytogenetic detection of FRAXE, without molecular analysis, could result in misdiagnosis of fragile X syndrome.

Cells, Cultured↗

PubMed1995

Molecular genetic analysis of mentally retarded males with features of the fragile-X syndrome.

The fragile-X[fra(X)] or Martin-Bell syndrome is the most common familial cause of mental retardation and is characterized by the presence of an Xq27.3 chromosome fragile site. Unstable DNA sequences representing large increases in the number of CGG trinucleotide DNA base repeats of the FMR-1 gene are located at the fragile site and responsible for the fra(X) syndrome. In order to identify whether cytogenetically normal yet mentally retarded males without a known cause of their retardation had expansion of the CGG repeat segment of the FMR-I gene, molecular genetic studies using Southern hybridization were performed with two DNA probes (fxa241 and Ox1.9) following digestion of genomic DNA from each patient with restriction enzymes Pstl and EcoRl/Eagl, respectively. DNA studies were performed on 20 (12.3%) out of 162 (122 white and 40 black people) cytogenetically normal mentally retarded males without a known cause of their retardation, but with high anthropometric discriminant values and/or clinical checklist scores identified previously and consistent with the fra(X) syndrome. None of the 20 males showed expansion of the CGG repeat of the FMR-1 gene detectable with the two probes used in this study. While heterogeneous single base pair substitutions, or small deletions or insertions in the FMR-I gene could exist in our patients, aberrations in other X-linked mental retardation genes, not identified to date but whose gene product can produce a phenotype similar to fra(X), either independently or in conjunction with the recently identified FMR-I protein, should be considered and are under investigation. Our study supports the idea that major FMR-I gene expansion detectable with Southern hybridization is rare in cytogenetically normal mentally retarded males, including those with physical and behavioural features seen in the fra(X) syndrome.

Adolescent↗

PubMedDate not supplied

Discordant genetic changes in ovarian and endometrial endometrioid carcinomas: a potential pitfall in molecular diagnosis.

Endometrioid carcinoma simultaneously involving ovaries as well as the uterine corpus may present a diagnostic dilemma because of the difficulty in determining whether the lesions are separate primary tumors or metastases. It has been reported that the detection of clonality using microsatellite markers may be useful in solving this dilemma. To determine the usefulness of this technique, we compared the genetic alterations in microsatellite markers present in matched pairs of ovarian tumors from 12 patients. The study includes four ovarian cancer FIGO stage I and eight stage III/IV patients, and four patients also with independent endometrial carcinoma of the uterus. DNA from paraffin-embedded tissue was extracted and amplified using a multiplex polymerase chain reaction, after which the status of microsatellite instability and loss of heterozygosity in four microsatellite loci (BAT25, BAT26, D17S250, and D5S346) were determined. In the four patients with stage I ovarian cancer, four microsatellite markers were identical in one patient and three were identical in the remaining three patients. In high-stage patients, three markers were identical in at least 4/8 cases. In three of four patients with uterine involvement, three of the four markers were identical in the uterine tumor and one of the corresponding ovarian tumors. These results suggest that genetic discordance does not indicate independent origin or metastasis of the tumor but instead a progression of genetic changes at separate sites probably due to the marked genetic instability existing in these tumors. Because of these discordant genetic changes, great caution should be taken when distinguishing between primary and metastatic tumors on the basis of microsatellite markers.

Adult↗

PubMed1993

Cataract and myotonic dystrophy: the role of molecular diagnosis.

Myotonic dystrophy (dystrophia myotonica), the commonest and most variable of the muscular dystrophies of adult life, has long been known to be associated with cataract, while slit-lamp examination for specific lens opacities has been one of the principal methods of presymptomatic detection of gene carriers. The recent discovery that the myotonic dystrophy mutation is an unstable DNA sequence, composed of varying numbers of CTG triplet repeats, now allows a specific molecular test for this disorder, as well as explaining the phenomenon of anticipation. A series of case reports is presented to illustrate the important practical applications of this development in relation to ophthalmic aspects of the disorder. Reassessment of the specificity of the ophthalmic changes may be required and it will be important for molecular analysis to be used alongside ophthalmic studies, when determining whether family members carry the mutation for myotonic dystrophy.

Adult↗

PubMed1993

Guidelines for the diagnosis of fragile X syndrome. National Fragile X Foundation.

Direct DNA analysis of the fragile X mutation has become available with the isolation of DNA probes that detect the unstable DNA sequence containing the CGG repeat. We present the various alternatives of combinations of probes and enzymes that can be used for the diagnosis of fragile X syndrome. An overview is given of all the different available probes. A different protocol is presented for postnatal and prenatal diagnosis of fragile X syndrome. This includes Southern blot analysis as well as direct analysis of the CGG repeat by PCR amplification. We discuss the role of constitutional cytogenetic analysis in the diagnosis of mentally retarded subjects and cytogenetic analysis for the diagnosis of fragile X syndrome.

Adult↗

PubMed1993

Prenatal diagnosis of a hypermethylated full fragile X mutation in chorionic villi of a male fetus.

Fragile X syndrome, one of the most common human genetic diseases, is characterised by a unique genetic mechanism which involves dynamic mutation because of a heritable unstable DNA sequence and abnormal DNA methylation. Direct detection of the dynamic mutation and its methylation status at the DNA level would facilitate reliable tests for prenatal and postnatal diagnosis of the disease and for carrier detection. However, it has been suggested that DNA methylation can not be used as the basis for prenatal diagnosis as the CpG island is not always methylated in chorionic villus DNA. We report here a male fetus exhibiting both extensive somatic heterogeneity and abnormal hypermethylation of the full fragile X mutation in chorionic villus DNA as well as in fetal tissue DNA. Our results indicate that both somatic heterogeneity and hypermethylation of the full fragile X mutation are events that are clearly detectable in the 11th to 12th week of pregnancy.

Blotting, Southern↗