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PubMed2026

Loss of interruption in the HTT CAG repeat is associated with somatic expansion and loss of medium spiny neurons in Huntington's disease.

Synonymous loss-of-interruption variants in the expanded CAG repeat sequence of Huntingtin (HTT) accelerate the clinical onset and progression of Huntington's disease (HD). Medium spiny neurons (MSNs) are gradually lost in HD and undergo selective somatic CAG expansion, but it is unclear how somatic expansion relates to MSN pathology. Here, we show that MSNs with large (111-150 CAG) and very large (>150 CAG) somatic expansions are rare in early manifest HD but accumulate in proportion with duration of disease. In patients with the deleterious CAG-CCG loss-of-interruption (CAG-CCG LOI) modifier, the proportion of MSNs with large and very large expansions is increased ∼5-fold despite reduced small somatic expansions in blood, and caudate MSN counts are reduced. Our findings suggest that increased somatic CAG expansion contributes to accelerated striatal MSN pathology and onset of HD but that MSNs with very large genomic CAG expansions can persist among surviving neurons of the HD brain.

Huntington’s disease↗
PubMed2005

Interruptions in the expanded ATTCT repeat of spinocerebellar ataxia type 10: repeat purity as a disease modifier?

Spinocerebellar ataxia type 10 (SCA10) is one of numerous genetic disorders that result from simple repeat expansions. SCA10 is caused by expansion of an intronic ATTCT pentanucleotide repeat tract. It is clinically characterized by progressive ataxia, seizures, and anticipation, which can vary within and between families. We report two SCA10 families showing distinct frequencies of seizures and correlations of repeat length with age at onset. One family displayed uninterrupted ATTCT expansions, whereas the other showed multiple interruptions of the repeat by nonconsensus repeat units, which differed both in the length and/or sequence of the repeat unit. Disease-causing microsatellite expansions have been assumed to be composed of uninterrupted pure repeats. Our findings for SCA10 challenge this convention and suggest that the purity of the expanded repeat element may be a disease modifier.

Age of Onset↗
PubMed2006

Evolutionary scenario for acquisition of CAG repeats in human SCA1 gene.

We investigated the CAG repeat sequence of the spinocerebellar ataxia type 1 (SCA1) gene in various species of primates to reveal how human has acquired the repeat structure with interruptions. Our results demonstrate no repetitive structure in the region corresponding to the human CAG repeats in prosimians and New World monkeys like in rodents, perfect (uninterrupted) CAG repeats in Old World monkeys, and interrupted CAG repeats in hominoids. Comparative analysis on the secondary structures of the primate SCA1 transcripts suggests the human prototype was built in the common ancestor of simians. We show an evolutionary scenario for acquisition of CAG repeats with interruptions in the human SCA1 gene.

Amino Acid Sequence↗
PubMed2005

SSR allelic variation in almond (Prunus dulcis Mill.).

Sixteen SSR markers including eight EST-SSR and eight genomic SSRs were used for genetic diversity analysis of 23 Chinese and 15 international almond cultivars. EST- and genomic SSR markers previously reported in species of Prunus, mainly peach, proved to be useful for almond genetic analysis. DNA sequences of 117 alleles of six of the 16 SSR loci were analysed to reveal sequence variation among the 38 almond accessions. For the four SSR loci with AG/CT repeats, no insertions or deletions were observed in the flanking regions of the 98 alleles sequenced. Allelic size variation of these loci resulted exclusively from differences in the structures of repeat motifs, which involved interruptions or occurrences of new motif repeats in addition to varying number of AG/CT repeats. Some alleles had a high number of uninterrupted repeat motifs, indicating that SSR mutational patterns differ among alleles at a given SSR locus within the almond species. Allelic homoplasy was observed in the SSR loci because of base substitutions, interruptions or compound repeat motifs. Substitutions in the repeat regions were found at two SSR loci, suggesting that point mutations operate on SSRs and hinder the further SSR expansion by introducing repeat interruptions to stabilize SSR loci. Furthermore, it was shown that some potential point mutations in the flanking regions are linked with new SSR repeat motif variation in almond and peach.

Alleles↗
PubMed1992

A bipartite DNA binding domain composed of direct repeats in the TATA box binding factor TFIID.

Point mutations in residues comprising the interrupted direct repeats of TFIID eliminated DNA binding in an electrophoretic mobility shift assay. In contrast, mutations in nonconserved residues within the direct repeat regions or in lysine residues comprising the intervening basic repeat had no effect on DNA binding. However, small spacing changes (addition or deletion of one to three residues) in the basic repeat eliminated DNA binding. These results argue for a bipartite DNA binding domain composed of direct repeats with a strict spacing and orientation. Surprisingly, some direct repeat mutations that inhibited DNA binding failed to show a corresponding inhibition of basal transcription, indicating compensating interactions of TFIID with other general factors. The implications of these and other recent results for TFIID structure, promoter recognition, and interactions with other factors are discussed.

Amino Acid Sequence↗
PubMed2001

GGA*TCC-interrupted triplets in long GAA*TTC repeats inhibit the formation of triplex and sticky DNA structures, alleviate transcription inhibition, and reduce genetic instabilities.

Large expansions of GAA.TTC repeats in the first intron of the frataxin (X25) gene are the principal mutation responsible for Friedreich's ataxia (FRDA). Sticky DNA, based on R.R.Y triplexes, was found at the expanded GAA.TTC repeats from FRDA patients. The (GAAGGA.TCCTTC)(65) repeat occurs in the same frataxin locus but is nonpathogenic and does not form sticky DNA. To elucidate the behavior of sticky DNA, we introduced various extents of GGA.TCC interruptions into the long GAA.TTC repeat. More than 20% of GGA.TCC interruptions abolished the formation of sticky DNA. However, the GAA.TTC repeats with less than 11% of GGA.TCC interruptions formed triplexes and/or sticky DNA similar to the uninterrupted repeat sequence. These triplexes showed different P1 nuclease sensitivities, and the GGA.TCC interruptions were slightly more sensitive than the surrounding GAA.TTC repeats. Furthermore, genetic instability investigations in Escherichia coli revealed that a small number (4%) of interruptions substantially stabilized the long GAA.TTC tracts. Furthermore, the greater the extent of interruptions of the GAA.TTC repeats, the less inhibition of in vitro transcription was observed, as expected, based on the capacity of interruptions to inhibit the formation of sticky DNA. We propose that the interruptions introduce base mismatches into the R.R.Y triplex, which explains the observed chemical and biological properties.

Base Sequence↗
PubMed1999

A study of the continence mechanism of the external urethral sphincter with identification of the voluntary urinary inhibition reflex.

PURPOSE: The role of the external urethral sphincter in the opposition and interruption of the act of voiding was investigated. MATERIALS AND METHODS: The study included 7 men and 5 women with a mean age plus or minus standard deviation of 38.6 +/- 11.2 years. The bladder was filled with saline up to the urge sensation. Detrusor and posterior urethral pressures were recorded before and upon resisting the reflex detrusor contraction, and upon interrupting voiding by voluntary external urethral sphincter contraction. The test was repeated by interrupting the urinary stream with external urethral sphincter electrostimulation. The electromyography response of the internal urethral sphincter to the suppression and interruption of voiding was documented before and after internal urethral sphincter anesthetization. RESULTS: Suppression of the reflex detrusor contraction as well as of urinary stream interruption by external urethral sphincter contraction voluntarily or by electrostimulation resulted in a significant detrusor pressure decrease (p <0.01) and urethral pressure increase (p <0.001). Internal urethral sphincter electromyography activity, which normally disappears during voiding, was still present. After internalurethral sphincter anesthetization subjects suppressed the reflex detrusor contraction by voluntary external urethral sphincter contraction for a mean of 62.6 +/- 9.6 seconds, after which involuntary voiding occurred. The internal urethral sphincter showed no electromyography activity. CONCLUSIONS: The external urethral sphincter induces continence by preventing internal urethral sphincter relaxation at the detrusor contraction, which is suggested to be reflex in nature and is called the voluntary urinary inhibition reflex, and by mechanically compressing the urethra. Contraction of the external urethral sphincter, which is a striated muscle, mechanically occludes the urethra for a few seconds, by which time the detrusor has relaxed as an effect of the voluntary inhibition reflex.

Adult↗
PubMed2001

Structure of the Hodgkin's lymphoma-associated human CD30 gene and the influence of a microsatellite region on its expression in CD30(+) cell lines.

The CD30 antigen is a member of the tumor necrosis factor receptor (TNFR) family which is overexpressed on the surface of the tumor cells of Hodgkin's lymphoma, anaplastic large cell lymphoma (ALCL), and embryonal carcinoma of the testis. In this study the entire cd30 gene which is more than 24000 bp long and organized in eight exons was characterized by analyzing cosmid and phage lambda clones from human placental libraries with long-range polymerase chain reaction (PCR) and sequencing. Differences to other genes of the TNFR family were detected in the region encoding the extracellular domain of the cd30 gene. In nearly all other TNFR genes, the coding region of each cysteine-rich repeat is interrupted by one intron, i.e., the 3-4 cysteine-rich repeats of these receptors are encoded by at least 4-5 exons, whereas the six cysteine-rich repeats of the cd30 gene are encoded by two exons, i.e., each of these exons encode three cysteine-rich repeats. In addition, we also found a genetic polymorphism of tetranucleotide ATCC-repeats in the 5' part of the CD30 promoter. This region was amplified by PCR from seven CD30 overexpressing human lymphoid cell lines and five human tissues with an absent or very low CD30 expression. The amplification products showed length differences of more than 550 bp. The number of the ATCC-repeats was higher in CD30(+) cell lines than in normal tissues. Comparison of the individual PCR products in reporter gene assays revealed that the CD30 promoter activity increased with the length of this polymorphic region up to eightfold. The data suggest that the number of ATCC-repeats in the 5' region of the CD30 promoter modulates the regulation of CD30 expression.

Base Sequence↗
PubMed1967

Effects of continuous and interrupted radiation on microorganisms.

Various bacterial spores exhibited a wide range of radiation resistance to doses of 0.25 to 2.5 Mrad from a cobalt-60 radiation facility. Bacillus pumilus and Clos-tridium tetani were shown to have the highest degree of resistance when compared with other bacterial sporeformers. B. subtilis E163 was the least resistant of the bacterial spores studied. Dried spores contained on cellulose discs were more readily destroyed by gamma-rays than were wet spores under similar conditions. Mycobacterium tuberculosis was destroyed by radiation doses much lower than that required by the least resistant bacterial spores. Interrupted dosimetry tests performed with materials of various types showed that sutures and other similar materials were effectively sterilized when the total radiation dose was given in two separate exposures with periods of interruption of 1 to 19 days. When "agar dosimeters" were employed in similar interrupted dosimetry series, B. pumilus spores were recovered in a few tests after administration of a total combined dosage of 2.5 Mrad with interruption periods of 2 to 19 days. When the experiment was repeated with interruption for 14 days, no survivors were found after a total dose of 2.0 to 2.8 Mrad.

Bacillus↗
PubMed2000

Evolution of microsatellite alleles in four species of mice (genus Apodemus).

Microsatellite length variation was investigated at a highly variable microsatellite locus in four species of Apodemus. Information obtained from microsatellite allele sequences was contrasted with allele sizes, which included 18 electromorphs. Additional analysis of a 400-bp unique sequence in the flanking region identified 26 different haplotype sequences or "true" alleles in the sample. Three molecular mechanisms, namely, (1) addition/deletion of repeats, (2) substitutions and indels in the flanking region, and (3) mutations interrupting the repeat, contributed to the generation of allelic variation. Size homoplasy can be inferred for alleles within populations, from different populations of the same species, and from different species. We propose that microsatellite flanking sequences may be informative markers for investigating mutation processes in microsatellite repeats as well as phylogenetic relationships among alleles, populations, and species.

Alleles↗
PubMed1981

Coding region deletions associated with the major form of rDNA interruption in Drosophila.

The nucleotide sequences at and around the termini of 5 kb type 1 interruptions in three separate clones of D. melanogaster rDNA repeats have been determined, and have been compared with the sequence of the corresponding region of an insertion-free rDNA repeat. All three interrupted rDNA repeats contain a small deletion of 28S rRNA coding material at the left coding/insertion sequence junction. A second deletion was found in one of the three clones, ad other aberrations were suggested by the results of restriction enzyme digestions of unfractionated rDNA. The termini of 5 kb type 1 rDNA insertions in D. melanogaster were also compared with the corresponding regions of 28S rDNA interruptions in D. virilis: the insertion site is identical in the two species, but the termini of the two species' interruptions show no homology. I sequenced a 1.1 kb region of the 5 kb type 1 D. melanogaster rDNA interruption that covers the sequences of the 1 kb and 0.5 kb insertions. There is 98% homology between the rightmost 1 kb of the 5 kb interruption and the sequences of the shorter insertions. Data suggest that Drosophila rDNA interruptions arose as a transposable element, and that divergence had included length alterations generated by unequal crossing over.

Animals↗
PubMed1995

Size homoplasy and mutational processes of interrupted microsatellites in two bee species, Apis mellifera and Bombus terrestris (Apidae).

Similar microsatellite electromorphs (PCR products of the same size) can arise from independent mutational events. Such alleles are not identical by descent. This phenomenon, termed size homoplasy, was studied by sequencing electromorphs of two microsatellite loci in which the stretch of basic repeats is interrupted by different short (1-2 bp) DNA motifs. The number and position of these interruptions were established for electromorphs from closely and distantly related populations of honeybees and bumblebees. No sequence difference was found when electromorphs came from the same subspecies or from closely related subspecies, suggesting that they were probably identical by descent. In contrast, sequence differences were often detected in distantly related subspecies, showing that size homoplasy frequently occurs at this level of population differentiation. Size homoplasy is increased by limits to free length variation of alleles, a phenomenon that seems to act on interrupted microsatellites when comparing distantly related taxa, that is, honeybee subspecies from different evolutionary lineages. Electromorph sequences suggest that, within the scope of these limits, large mutation events have occurred frequently at both interrupted loci studied. In good agreement with the molecular data, computations based on the observed heterozygosity and number of electromorphs and simulation studies showed that neither locus fits the one-step stepwise mutant model (SMM). We speculate that interrupted microsatellites in general could be characterized by a higher variance in repeat number and consequently a lower homoplasy rate than pure ones. Hence, interrupted microsatellites should be most appropriate for investigating population differentiation and evolutionary relationship between relatively distant populations.

Alleles↗
PubMed1988

Regional myocardial volume alterations induced by brief repeated coronary occlusion in conscious dogs.

The purpose of this study was to evaluate whether brief repeated coronary occlusions induce changes in regional myocardial geometry at rest. Five conscious dogs were instrumented for the measurement of subendocardial segment length and transmural wall thickness in the ischemic area, subendocardial segment length in the normally perfused area, coronary flow and left ventricular pressure. After recovery from surgery, 180 (mean) 2 min coronary occlusions were given over a period of 20 days. The heart rate at rest, left ventricular peak systolic and end-diastolic pressures and peak positive first derivative of left ventricular pressure (dP/dt) remained unchanged throughout the experiment. In the normal area, the end-diastolic segment length at rest did not change significantly. By contrast, in the ischemic area, at 14 days after the initiation of repeated coronary occlusion, the end-diastolic regional cross-sectional area (product of segment length and wall thickness) at rest had increased by 9.7% (p less than 0.05); thereafter it decreased to 6.5% (p less than 0.05) above the value at rest before repeated occlusion despite an additional 6 days of coronary occlusions. At 10 days after the interruption of repeated occlusion, this value had regressed to 4.3% (p = NS) above control. These findings suggest the occurrence of regional myocardial hypertrophy confined to the ischemic area in response to the periodic ischemic stimulus.

Animals↗
PubMed1997

Trinucleotide repeats affect DNA replication in vivo.

(CGG)n.(CCG)n and (CTG)n.(CAG)n repeats of varying length were cloned into a bacterial plasmid, and the progression of the replication fork through these repeats was followed using electrophoretic analysis of replication intermediates. We observed stalling of the replication fork within repeated DNAs and found that this effect depends on repeat length, repeat orientation relative to the replication origin and the status of protein synthesis in a cell. Interruptions within repeated DNAs, similar to those observed in human genes, abolished the replication blockage. Our results suggest that the formation of unusual DNA structures by trinucleotide repeats in the lagging-strand template may account for the observed replication blockage and have relevance to repeat expansion in humans.

Chloramphenicol↗
PubMed1999

Tracing the origin of HLA-DRB1 alleles by microsatellite polymorphism.

We analyzed the origin of allelic diversity at the class II HLA-DRB1 locus, using a complex microsatellite located in intron 2, close to the polymorphic second exon. A phylogenetic analysis of human, gorilla, and chimpanzee DRB1 sequences indicated that the structure of the microsatellite has evolved, primarily by point mutations, from a putative ancestral (GT)x(GA)y-complex-dinucleotide repeat. In all contemporary DRB1 allelic lineages, with the exception of the human *04 and the gorilla *08 lineages, the (GA)y repeat is interrupted, often by a G-->C substitution. In general, the length of the 3' (GA)y repeat correlates with the allelic lineage and thus evolves more slowly than a middle (GA)z repeat, whose length correlates with specific alleles within the lineage. Comparison of the microsatellite sequence from 30 human DRB1 alleles showed the longer 5' (GT)x to be more variable than the shorter middle (GA)z and 3' (GA)y repeats. Analysis of multiple samples with the same exon sequence, derived from different continents, showed that the 5' (GT)x repeat evolves more rapidly than the middle (GA)z and the 3' (GA)y repeats, which is consistent with findings of a higher mutation rate for longer tracts. The microsatellite-repeat-length variation was used to trace the origin of new DRB1 alleles, such as the new *08 alleles found in the Cayapa people of Ecuador and the Ticuna people of Brazil.

Alleles↗
PubMed2001

CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms.

Spinocerebellar ataxia 2 (SCA2) is an autosomal dominant neurodegenerative disorder that results from the expansion of a cryptic CAG repeat within the exon 1 of the SCA2 gene. The CAG repeat in normal individuals varies in length from 14 to 31 repeats and is frequently interrupted by one or more CAA triplets, whereas the expanded alleles contain a pure uninterrupted stretch of 34 to 59 CAG repeats. We have previously reported the presence of a limited pool of 'ancestral' or 'at risk' haplotypes for the expanded SCA2 alleles in the Indian population. We now report the identification of two novel single nucleotide polymorphisms (SNPs) in exon 1 of the SCA2 gene and their characterization in 215 normal and 64 expanded chromosomes. The two biallelic SNPs distinguished two haplotypes, GT and CC, each of which formed a predominant haplotype associated with normal and expanded SCA2 alleles. All the expanded alleles segregated with CC haplotype, which otherwise was associated with only 29.3% of the normal chromosomes. CAA interspersion analysis revealed that majority of the normal alleles with CC haplotype were either pure or lacked the most proximal 5' CAA interruption. The repeat length variation at SCA2 locus also appeared to be polar with changes occurring mostly at the 5' end of the repeat. Our results demonstrate that CAA interruptions play an important role in conferring stability to SCA2 repeat and their absence predisposes alleles towards instability and pathological expansion. Our study also provides new haplotypes associated with SCA2 that should prove useful in further understanding the mutational history and mechanism of repeat instability at the SCA2 locus.

Alleles↗
PubMed1992

Substitution of arginine for glycine 325 in the collagen alpha 5 (IV) chain associated with X-linked Alport syndrome: characterization of the mutation by direct sequencing of PCR-amplified lymphoblast cDNA fragments.

A large kindred with adult-type X-linked Alport syndrome was studied with regard to a defect in the recently described COL4A5 collagen gene. Southern blot analysis with COL4A5 cDNA probes showed loss of a MspI restriction site. Direct sequencing of cDNA amplified from lymphoblast mRNA demonstrated a single-base substitution converting a glycine codon to arginine at position 325 in the alpha 5 chain of type IV collagen. The triple-helical collagenous domain of alpha 5(IV), characterized by a Gly-X-Y repeat sequence, is interrupted 22 times by noncollagenous sequences. The mutation creates an additional interruption in the Gly-X-Y repeat motif, between interruptions 4 and 5. It is interesting that such glycine substitutions inside the COL1A1 or COL1A2 genes have been associated with many cases of osteogenesis imperfecta. This gly325-to-arg substitution presumably alters the triple-helix formation, and, in turn, modifies the ultrastructural and functional characteristics of the type IV collagen network inside the glomerular basement membrane.

Adult↗