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PubMed1997

Somatic instability of the myotonic dystrophy (CTG)n repeat during human fetal development.

Myotonic dystrophy is characterised by the striking level of somatic heterogeneity seen between and within tissues of the same patient, which probably accounts for a significant proportion of the pleiotropy associated with this disorder. The congenital form of the disease is associated with the largest (CTG)n repeat expansions. We have investigated the timing of instability of myotonic dystrophy (CTG)n repeats in a series of congenitally affected fetuses and neonates. We find that during the first trimester the repeat is apparently stable and that instability only becomes detectable during the second and third trimesters. In our series repeat instability is apparent only after 13 weeks gestational age and before 16 weeks. The appearance of heterogeneity shows some tissue specificity, with heart most commonly having the largest expansion. The degree of heterogeneity is not correlated with initial expansion size as gauged by chorionic villus and blood (CTG)n repeat sizes.

Embryonic and Fetal Development↗
PubMed2000

Transgenic mice carrying large human genomic sequences with expanded CTG repeat mimic closely the DM CTG repeat intergenerational and somatic instability.

Myotonic dystrophy (DM) is caused by a CTG repeat expansion in the 3'UTR of the DM protein kinase (DMPK) gene. A very high level of instability is observed through successive generations and the size of the repeat is generally correlated with the severity of the disease and with age at onset. Furthermore, tissues from DM patients exhibit somatic mosaicism that increases with age. We generated transgenic mice carrying large human genomic sequences with 20, 55 or >300 CTG, cloned from patients from the same affected DM family. Using large human flanking sequences and a large amplification, we demonstrate that the intergenerational CTG repeat instability is reproduced in mice, with a strong bias towards expansions and with the same sex- and size-dependent characteristics as in humans. Moreover, a high level of instability, increasing with age, can be observed in tissues and in sperm. Although we did not observe dramatic expansions (or 'big jumps' over several hundred CTG repeats) as in congenital forms of DM, our model carrying >300 CTG is the first to show instability so close to the human DM situation. Our three models carrying different sizes of CTG repeat provide insight on the different factors modulating the CTG repeat instability.

3' Untranslated Regions↗
PubMed2003

Somatic instability of the androgen receptor CAG repeat in a normal female.

The polyglutamine repeat disorders represent a family of degenerative neurological diseases which are characterized by expansions of tandemly repeated CAG repeats. Investigations have demonstrated that in Huntington disease, dentatorubral pallidoluysian atrophy, and the spinocerebellar ataxias type 1, 2, and 3, the polyglutamine expansions show both meiotic and mitotic instability. However, previous studies have suggested that the polyglutamine motif within exon 1 of the androgen receptor gene (AR) which expands in cases of spinobulbar muscular atrophy differs in that it is apparently mitotically stable. During linkage analysis in a family with FG syndrome, a rare condition mapped to Xq12-q22.1, we detected the presence of an unusually small AR allele segregating within the pedigree. Sequencing, cytogenetic analysis, and PCR of flanking markers indicate that this allele arose by a somatic contraction of seven CAG repeats in the proband's mother, representing the first report of mitotic instability of an AR CAG repeat of normal size.

Adult↗
PubMed1986

Germ line and somatic instability of a white mutation in Drosophila mauritiana due to a transposable genetic element.

A spontaneous white mutation recovered in Drosophila mauritiana is unstable and reverts to normal eye color at a frequency greater than 4 per 1,000 X-chromosomes. Germ line reversion occurs at a high rate in D. mauritiana males and in interspecific hybrid females, while the rate is depressed in D. mauritiana females. These events are not restricted to the germ line, as cases of variegated patterns of eye pigmentation, indicating somatic reversion, are recovered at a frequency comparable to that of the male germ line reversion rate. Germ line reversion events are genetically stable, while the somatic variegation patterns are not heritable. The patterns of eye pigment variegation produced suggests that reversion events are occurring throughout development. Whole genome DNA digests blotted and probed with the cloned D. melanogaster white gene indicate that this unstable white mutation in D. mauritiana is associated with an insertion of DNA that is lost upon reversion to wild type, indicating that this DNA insert is in fact a transposable element.

Animals↗
PubMed1996

Segregation of the fragile X mutation from a male with a full mutation: unusual somatic instability in the FMR-1 locus.

Fragile X syndrome is associated with an unstable CGG-repeat in the FMR-1 gene. There are few reports of affected males transmitting the FMR-1 gene to offspring. We report on a family in which the propositus and his twin sister each had a full mutation with abnormal methylation. Their mother had an FMR-1 allele in the normal range and a large premutation, with normal methylation. The maternal grandmother had two normal FMR-1 alleles. The maternal grandfather had an unusual somatic FMR-1 pattern, with allele size ranging from premutation to full mutation. No allele was detectable by PCR analysis. Multiple Southern blot analyses identified a hybridization pattern that originated at a distinct premutation band and extended into the full mutation range. Methylation studies revealed a mosaic pattern with both unmethylated premutations and methylated full mutations. This individual declined formal evaluation but did not finish high school and has difficulty in reading and writing. The size of the premutation FMR-1 allele passed to his daughter is larger than his most prominent premutation allele. This is most likely due to gonadal mosaicism similar to that in his peripheral lymphocytes. Alternatively, this expansion event may have occurred during his daughter's early embryonic development and this large premutation allele is mitotically unstable. This pattern of FMR-1 alleles in a presumably mildly affected male is highly unusual. These findings are consistent with the absence of transmission of a full fragile X mutation through an expressing male. Studies of tissue specific FMR-1 allele expansion and FMR-1 protein expression on this individual should help to determine the correlation of the molecular findings with the phenotypic effects.

Alleles↗
PubMed2005

Haplotype diversity and somatic instability in normal and expanded SCA8 alleles.

Spinocerebellar ataxia type 8 (SCA8) is an autosomal dominant late-onset neurodegenerative disorder, belonging to the group of diseases caused by trinucleotide repeat expansions. SCA8 remains one of the most intriguing SCAs, regarding the reduced disease penetrance, and the high instability and poorly understood functional meaning of the (CTA)(n)(CTG)(n) expansion. We performed haplotype and sequencing analysis in a large region, encompassing the repeat, in four SCA8 and 20 control Portuguese families. The results from the haplotype study including the combined repeat and six SNP markers showed two different haplotypes, AG-Exp-GTTG and AG-Exp-CTTG, in the SCA8 families. Among the control population, these were also the most frequent, in a total of five haplotypes found unequally distributed throughout repeat sizes. From cloning fragments of control, unstable normal and expanded chromosomes, eleven different base substitutions were identified in exon A of the SCA8 gene. In some instances, somatic variability in repeat size or base composition was found for a same chromosome, regardless of its normal or expanded nature. In conclusion, our results in Portuguese families with ataxia show that SCA8 expansions arose in common backgrounds; in addition, this region seems to be unstable beyond the repeat.

Alleles↗
PubMed2003

High somatic instability of a microsatellite locus in a clonal tree, Robinia pseudoacacia.

Robinia pseudoacacia L. is a clonal tree species. To investigate a mutation within eight microsatellite loci of R. pseudoacacia, we analyzed DNA samples obtained from different leaf samples within each ramet, leaves from ramets within the genet, and seeds. Of the eight loci, locus Rops15 (AG motif) displayed hypermutability. The mutation rates of Rops15 within each ramet, among ramets within the genet, and offspring were 6.27% (ranging from 0 to 31.1%), 6.11% (from 0 to 25.0%) and 3.78% (from 0 to 10.9%), respectively. The mutation rate increased with allele size (13-71 repeat units). The mutation patterns observed in Rops15 were distinctive in two ways. First, there was a significant bias toward additions over deletions, and both addition and deletion of single repeats were dominant at alleles with lengths less than 232 bp (63 repeats). Second, for the longest allele of 248 bp (71 repeats), the number of losses was higher than the number of gains. These observations suggest that the mutation patterns of microsatellites in R. pseudoacacia may follow a generalized stepwise mutation model, and that the tendency of long alleles to mutate to shorter lengths acts to prevent infinite growth. Finally, the observation of somatic hypermutability at locus Rops15 highlights the need for caution when using highly polymorphic microsatellites for population genetic structure and paternity analysis in tree species.

DNA Primers↗
PubMed2003

Somatic instability of the NF2 gene in schwannomatosis.

CONTEXT: Schwannomatosis is a newly described form of neurofibromatosis of unclear pathogenesis. PATIENT AND METHODS: We studied the NF2 locus on chromosome 22 in 7 tumor specimens resected from a 36-year-old man with schwannomatosis of the right ulnar nerve. RESULTS: Unrelated truncating NF2 gene mutations were detected in 4 tumor specimens. None of the NF2 mutations were present in the blood specimen. Loss of heterozygosity at the NF2 locus was seen in all tumors, and in every case the same allele was lost. Loss of distal chromosome 22 markers was variable. Fluorescence in situ hybridization results were consistent with monosomy 22 in 4 tumors and mitotic recombination or nondisjunction in 1. CONCLUSIONS: Molecular analysis of tumor specimens distinguishes schwannomatosis from other forms of neurofibromatosis. Further work is needed to understand the natural history and molecular biology of this condition.

Adult↗
PubMed1992

Somatic instability of a Drosophila chromosome.

A mitotically unstable chromosome, detectable because of mosaic expression of marker genes, was generated by X-ray mutagenesis in Drosophila. Nondisjunction of this chromosome is evident in mitotic chromosome preparations, and premature sister chromatid separation is frequent. The mosaic phenotype is modified by genetic elements that are thought to alter chromatin structure. We hypothesize that the mitotic defects result from a breakpoint deep in the pericentric heterochromatin, within or very near to the DNA sequences essential for centromere function. This unique chromosome may provide a tool for the genetic and molecular dissection of a higher eukaryotic centromere.

Animals↗
PubMed2002

Frequent germline mutations and somatic repeat instability in DNA mismatch-repair-deficient Caenorhabditis elegans.

Mismatch-repair-deficient mutants were initially recognized as mutation-prone derivatives of bacteria, and later mismatch repair deficiency was found to predispose humans to colon cancers (HNPCC). We generated mismatch-repair-deficient Caenorhabditis elegans by deleting the msh-6 gene and analyzed the fidelity of transmission of genetic information to subsequent generations. msh-6-defective animals show an elevated level of spontaneous mutants in both the male and female germline; also repeated DNA tracts are unstable. To monitor DNA repeat instability in somatic tissue, we developed a sensitive system, making use of heat-shock promoter-driven lacZ transgenes, but with a repeat that puts this reporter gene out of frame. In genetic msh-6-deficient animals lacZ+ patches are observed as a result of somatic repeat instability. RNA interference by feeding wild-type animals dsRNA homologous to msh-2 or msh-6 also resulted in somatic DNA instability, as well as in germline mutagenesis, indicating that one can use C. elegans as a model system to discover genes involved in maintaining DNA stability by large-scale RNAi screens.

Amino Acid Sequence↗
PubMed2004

Somatic and germline instability of the ATTCT repeat in spinocerebellar ataxia type 10.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder characterized by ataxia, seizures, and anticipation. It is caused by an expanded ATTCT pentanucleotide repeat in intron 9 of a novel gene, designated "SCA10." The ATTCT expansion in SCA10 represents a novel class of microsatellite repeat and is one of the largest found to cause human diseases. The expanded ATTCT repeat is unstably transmitted from generation to generation, and an inverse correlation has been observed between size of repeat and age at onset. In this multifamily study, we investigated the intergenerational instability, somatic and germline mosaicism, and age-dependent repeat-size changes of the expanded ATTCT repeat. Our results showed that (1) the expanded ATTCT repeats are highly unstable when paternally transmitted, whereas maternal transmission resulted in significantly smaller changes in repeat size; (2) blood leukocytes, lymphoblastoid cells, buccal cells, and sperm have a variable degree of mosaicism in ATTCT expansion; (3) the length of the expanded repeat was not observed to change in individuals over a 5-year period; and (4) clinically determined anticipation is sometimes associated with intergenerational contraction rather than expansion of the ATTCT repeat.

Age Distribution↗
PubMed2004

Triplet repeats and DNA repair: germ cell and somatic cell instability in transgenic mice.

This chapter describes methods for the isolation of specific cell types that reveal how and where expansion can occur. For the hereditary component of expansion, the male germ cell has proved useful in distinguishing processes that can contribute to expansion, as described in our article (Nature Genetics 27, 407, 2001). Mature spermatazoa (SZs) can be isolated directly from the epididymis. Haploid spermatids (STs), diploid spermatagonia (SGs), and tetraploid spermatocytes (SCs) can be removed from the testis and sorted by fluorescence-activity cell sorting (FACS); differences in DNA content and morphology allow resolution by fluorescence and light scattering. Repeat-length measurement can pinpoint the stage at which expansion occurs. Because the timing of meiosis and mitosis with respect to sperm development is known, the analysis can distinguish repair and replication processes. Furthermore, the possible contribution of Y- or X-specific factors can be evaluated by sorting X- and Y-bearing germ cells. To enable analysis of female germ cells, we describe methods for oocyte preparations and a method for the isolation of the eight-cell-stage embryo. Therefore, the methods described here can help to answer such questions as the timing during development of expansion, whether expansion is limited to a single period, whether both replication and repair contribute to instability, and the role of somatic instability in disease. If further expansion of the inherited allele contributes to the phenotype, then intervention in somatic tissue might be therapeutic.

Animals↗
PubMed2002

Identification of MARCKS, FLJ11383 and TAF1B as putative novel target genes in colorectal carcinomas with microsatellite instability.

Somatic frameshift mutations in some genes containing coding mononucleotide repeats (cMNRs) are well known characteristics of tumors with high microsatellite instability (MSI-H). We identified 22 novel and 11 known target genes containing cMNRs with a length of 10 or more nucleotides by using a systematic database search. Frameshift mutation analysis was performed with these 33 genes in 39 MSI-H and 24 microsatellite stable (MSS) colorectal carcinomas by assessing the mobility shifts of PCR products in gel electrophoresis and by sequencing. All the 39 MSI-H colorectal carcinomas, except one, showed mutations in more than one gene, while no mutations were found in 24 MSS colorectal carcinomas. Of these MSI-H tumors, 11 genes were mutated in more than 40%. The most frequently mutated novel genes were MARCKS (72%), FLJ11383 (74%) and TAF1B (82%). Biallelic inactivation in MARCKS and FLJ11383 was also frequent in MSI-H tumors. The observed mutation frequency of the 11 known target genes was compatible with that found by previous studies. The very high frequency of mutations, biallelic mutations and the predicted truncation of protein products suggests that mutations of MARCKS, FLJ11383 and TAF1B are selected, and play a role in the tumorigenesis of MSI-H colorectal carcinomas.

Base Sequence↗
PubMed1998

Microsatellite instability and somatic mutations in endometrial carcinomas.

Recently, microsatellite instability (MI) has been demonstrated in some types of human cancers. In this study, we attempted to determine the frequency of MI in endometrial cancers and evaluate whether replication error (RER)-positive phenotype is correlated with known genetic mutations or the aberrations of other pathways in endometrial cancers. Seventy-two primary endometrial cancers were examined for microsatellite instability. Eleven tumors (15%) had RERs at two or more microsatellite loci, suggesting that generalized MI may be a molecular manifestation of endometrial cancers. We next examined whether the MI was associated with changes in the K-ras protooncogene, p53 tumor suppressor gene, and 18q LOH, which were frequently detected in endometrial cancers. The MI did not confer the potential to produce point mutations in the K-ras gene or 18q LOH, whereas the data were insufficient to identify the correlation between MI and p53 mutations in the cancers. These results suggest the presence of multiple mutation subsets that act in a complementary fashion in endometrial cancer development.

Chromosomes, Human, Pair 18↗
PubMed2002

250 CTG repeats in DMPK is a threshold for correlation of expansion size and age at onset of juvenile-adult DM1.

Myotonic dystrophy type 1 (DM1) is associated with an expansion of CTG repeats in the 3'UTR of the DMPK gene. It is accepted, as in other trinucleotide diseases, that the number of the repeats is correlated with age at onset and severity of the disease. However, assessment of genotype-phenotype correlation in DM1 is complicated with the expansion-biased somatic instability of mutant alleles over time and difficulties in precise assessment of the number of repeats by standard Southern blot hybridization. In order to clarify this issue we defined DM1 expansion size in lymphocytes by three parameters: size of progenitor, average, and largest allele, using a more precise small-pool/long-range PCR technique. We found a negative linear correlation of age at onset and average expansion size in juvenile-adult DM1 patients (35 out of 46) whose progenitor allele is less than 245 repeats long. Our result favors the hypothesis of the existence of a threshold in the progenitor allele size beyond which number of CTG repeats does not influence age at onset. Potential clinical significance is that the average allele size could be a useful indicator for the age at onset in juvenile-adult DM1 patients with relatively short progenitor allele. To test whether somatic instability of mutant alleles influences the progression of DM1, patients were divided in three phenotypic classes according to the severity of neuromuscular symptoms. We showed that the largest expansion in each DM1 phenotypic class reflects somatic instability of mutant allele over time independently of progenitor allele size and patient's age at sampling. The mean of the largest expansion was significantly different between phenotypic classes, implying the possible association between expansion-biased somatic instability of mutant alleles over time and progression of neuromuscular symptoms.

Adult↗
PubMed2004

Detection of microsatellite instability during somatic embryogenesis of oak (Quercus robur L.).

Five microsatellite loci (QpZAG1/5, QpZAG9, QpZAG36, MSQ4, MSQ13) were used to test for genetic stability of three somatic embryogenic culture lines of Quercus robur L. and plantlets derived therefrom. DNA variation was detected among somatic embryos within all embryogenic lines, whereas no genetic instability was found among the regenerated plants. Two microsatellite loci revealed variation, and a locus-dependent instability was observed. The most polymorphic and useful microsatellite locus for detecting genetic variation was QpZAG9, with 28.5% of the investigated loci being variable.

Agriculture↗
PubMed1993

Microsatellite instability in bladder cancer.

Somatic instability at microsatellite repeats was detected in 6 of 200 transitional cell carcinomas of the bladder. Instabilities were apparent as changes in (GT)n repeat lengths on human chromosome 9 for four tumors and as alterations in a (CAG)n repeat in the androgen receptor gene on the X chromosome for three tumors. Single locus alterations were detected in three tumors, while three other tumors revealed changes in two or more loci. In one tumor we found microsatellite instability in all five loci analyzed on chromosome 9. The alterations detected were either minor 2-base pair changes or larger (> 2 base pairs) alterations in repeat length. All six tumors were low stage (Ta-T1), suggesting that these alterations can occur early in bladder tumorigenesis.

Base Sequence↗