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At least 865 records · Page 48Linked to original sources
PubMed1998

The genomic breakpoint and chimeric transcripts in the EWSR1-ETV4/E1AF gene fusion in Ewing sarcoma.

Chromosome translocation creates a fusion between the EWSR1 gene and an ETS family gene. The fusion between these two genes is a characteristic feature of Ewing sarcoma. We previously identified a fourth translocation, t(17;22)(q12;q12), in genomic DNA isolated from cells of patients affected with Ewing sarcoma. The discovery of this translocation suggested that there might be a novel EWSR1-ETV4 fusion gene. In the present study, we determined the genomic breakpoint and characterized the chimeric transcript of the EWSR1-ETV4 fusion gene in two t(17;22) Ewing sarcomas. Reverse transcriptase-PCR assay showed an in-frame fusion between the 5'-terminal region of EWSR1 and the 3' end of ETV4 (alias E1AF, PEA3); the chimeric transcript could thus serve as a template for expression of a protein composed of the N-terminal portion of EWSR1 fused to the DNA-binding domain of ETV4. Long PCR and sequence analysis of genomic DNA revealed that either exon 8 or intron 7 of EWSR1 is fused to the same intron of ETV4 in both tumors. Several palindromic oligomer sequences were found close to the breakpoints in both genes. The 159-bp Alu-like sequence was repeated in the breakpoint region of the ETV4 gene. These observations suggest a mechanism of EWSR1-ETV4 gene fusion.

Alu Elements↗
PubMed1999

Chromosomal localization of zebrafish AluI repeats by primed in situ (PRINS) labeling.

Two zebrafish AluI repeats were localized in metaphase chromosomes by means of the primed in situ (PRINS) labeling technique, using oligonucleotide primers based on published sequences. An AT-rich, tandemly repeated, long AluI restriction fragment (RFAL1) labeled the (peri)centromeric regions of all chromosomes. The GC-rich short fragment (RFAS) was found to be localized in the paracentromeric regions of 17 chromosome pairs, which were mostly subtelocentric. The RFAS labeling pattern generally fits the previously described chromomycin A3 (CMA3) staining pattern. The differential composition of heterochromatin in zebrafish chromosomes is discussed.

Alu Elements↗
PubMed1999

Assignment of human teratocarcinoma derived growth factor (TDGF) sequences to chromosomes 2q37, 3q22, 6p25 and 19q13.1.

The human teratocarcinoma derived growth factor 1 (TDGF1) gene maps on chromosome (Chr) 3p21.3. One pseudogene (TDGF3) maps on Chr Xq21-->q22. We now report the nucleotide sequence and chromosome location of three additional TDGF pseudogenes. The three new sequences (TDGF2, TDGF4 and TDGF5) are truncated at the 5' end and have accumulated several point mutations, deletions and insertions. TDGF2, TDGF4 and TDGF6 map on Chrs 2q37, 6p25 and 3q22, respectively. Finally, Southern blot analysis of DNA from normal individuals shows a highly variable restriction pattern of the TDGF sequences.

Alu Elements↗
PubMed1999

Hereditary desmoid disease in a family with a germline Alu I repeat mutation of the APC gene.

Two families with autosomal dominantly inherited desmoid tumors have recently been shown to have germline mutations at the 3' end of the APC gene. We subsequently identified an Amish family with autosomal dominantly inherited desmoid tumors. Genetic analysis performed on one family member, a 47-year-old man with multiple desmoid tumors and no colon polyps, revealed a protein truncating mutation in the middle of the APC gene. The truncating mutation is the result of a 337-bp insertion of an Alu I sequence into codon 1526 of the APC gene. The presence of a poly(A) tail at the 3' end of the insertion suggests that the Alu I sequence was inserted by a retrotranspositional event. Germline insertions of Alu I sequences have occasionally been reported to cause other genetic diseases including type I neurofibromatosis, hereditary site-specific breast cancer (BRCA2), and hemophilia B. However, this is the first report of a germline mutation of the APC gene resulting from an Alu I insertion.

Adenomatous Polyposis Coli↗
PubMed2004

Repair rates of R-band, G-band and C-band DNA in murine and human cultured cells.

Repair of cyclobutane pyrimidine dimers (CPDs) in cultured neonatal human fibroblasts and in Mus spretus x M. castaneus F1 neonatal skin fibroblasts was analyzed after UVC-irradiation by cleavage with T4 endonuclease V cyclopyrimidine dimer glycosylase, alkaline-agarose gel electrophoresis, and Southern blotting. The blots were sequentially probed with 32P-labeled Alu, or B2, to preferentially illuminate R-band DNA, by L1 to preferentially illuminate G-band DNA, and by satellite DNA to illuminate C-band DNA. These three different DNA populations showed slightly different global nucleotide excision repair rates that are in the order of speed, R-band DNA > G-band DNA > C-band DNA. Fibroblasts from out-bred neonatal mice and humans showed similar band-specific repair rate ratios and the global repair rate of murine fibroblasts was almost as rapid as that of the human fibroblasts. The mass distribution of the human Alu-probed signal was further analyzed. Gel mobility data was fitted to a logistic equation to include all M(r) values. Hypothetical distributions of DNA randomly cleaved to a particular number-average molecular weight were fit to the logistic gel mobility function to determine how such a randomly cleaved distribution of a particular cleavage frequency would be displayed along the experimental gel. This revealed a rapidly repaired kinetic fraction that represented 17% of the Alu-probed signal (R-band DNA), almost none of the L1 probed signal (G-band DNA), and reflects transcription coupled repair of active genes. The remaining Alu-probed DNA showed a random distribution of UVC-induced CPDs throughout all stages of global nucleotide excision repair. The Alu-probed CPDs disappeared with an excellent fit to first order kinetics and with a half-life of seven hours.

Alu Elements↗
PubMed2004

Quantitative PCR analysis reveals a high incidence of large intragenic deletions in the FANCA gene in Spanish Fanconi anemia patients.

Fanconi anaemia is an autosomal recessive disease characterized by chromosome fragility, multiple congenital abnormalities, progressive bone marrow failure and a high predisposition to develop malignancies. Most of the Fanconi anaemia patients belong to complementation group FA-A due to mutations in the FANCA gene. This gene contains 43 exons along a 4.3-kb coding sequence with a very heterogeneous mutational spectrum that makes the mutation screening of FANCA a difficult task. In addition, as the FANCA gene is rich in Alu sequences, it was reported that Alu-mediated recombination led to large intragenic deletions that cannot be detected in heterozygous state by conventional PCR, SSCP analysis, or DNA sequencing. To overcome this problem, a method based on quantitative fluorescent multiplex PCR was proposed to detect intragenic deletions in FANCA involving the most frequently deleted exons (exons 5, 11, 17, 21 and 31). Here we apply the proposed method to detect intragenic deletions in 25 Spanish FA-A patients previously assigned to complementation group FA-A by FANCA cDNA retroviral transduction. A total of eight heterozygous deletions involving from one to more than 26 exons were detected. Thus, one third of the patients carried a large intragenic deletion that would have not been detected by conventional methods. These results are in agreement with previously published data and indicate that large intragenic deletions are one of the most frequent mutations leading to Fanconi anaemia. Consequently, this technology should be applied in future studies on FANCA to improve the mutation detection rate.

Alu Elements↗
PubMed2006

From East to West: patterns of genetic diversity of populations living in four Eurasian regions.

We have analyzed the distribution and patterns of the genetic diversity of eight Alu loci (ACE, ApoA1, PV92, TPA25, NBC27, NBC102, NBC148, and NBC182) in 1,049 individuals representing 16 populations of the Volga-Ural region (Bashkirs, Tatars, Komis, Maris, Mordvins, and Udmurts), Central Asia (Kazakhs, Uzbeks, and Uighurs), the North Caucasus (Karachays, Kumyks, Kuban Nogays, and Karanogays), and Central South Siberia (Yakuts, Kalmyks and Evenks). Geographic divide between Europe and Asia, e.g. the Ural Mountains and the Caspian Sea, can also be considered as a genetic boundary. The data indicates that the populations of the two boundary regions between Europe and Asia, the Volga-Ural region of Russia, and populations of the North Caucasus are more similar to European than to Asian populations. Finally, Siberian and Central Asian populations are genetically closely related to each other.

Alleles↗
PubMed2006

Influence of Angiotensin-converting enzyme polymorphism on neuropsychological subacute performance in moderate and severe traumatic brain injury.

Traumatic brain injury (TBI) frequently results in cerebrovascular lesions that may increase secondary damage and cause neuropsychological impairment. Previous studies suggest an association among the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE), cardiovascular disease, and cognitive performance. Clinical and experimental studies have demonstrated the beneficial effects of ACE inhibitor treatment on vascular injury, hypertension, brain ischemia, and cognitive functioning. In a sample of 73 moderate and severe TBI patients, the authors assessed whether cognitive sequelae differed in relation to the ACE I/D polymorphism. D allele carrier patients performed worse than those with I/I polymorphism on tests involving attention and processing speed. Findings suggest that the physiopathological changes associated with TBI may have greater consequences in ACE D allele carriers.

Adolescent↗
PubMed2003

Influence of the Alu-repeat I/D polymorphism in t-PA gene intron 8 on the stimulated t-PA release after venous occlusion.

Tissue type plasminogen activator (t-PA) is released from endothelium in both a constitutive and regulated fashion. In healthy subjects, an association between net t-PA release rate and a few t-PA gene polymorphisms, including the Alu-repeat I/D polymorphism in intron 8, was described. The possible influence of the Alu-repeat polymorphism on t-PA release was evaluated after a venous occlusion test (VO) in 82 patients showing an impaired fibrinolytic capacity associated with different arterial disease or with previous venous thrombosis, and in 50 healthy controls. Euglobulin lysis time, t-PA antigen (t-PA:Ag) and activity, PAI-1 antigen and activity plasma levels were assayed before and 20 minutes after VO; the Alu-repeat I/D polymorphism was determined by PCR. Defective fibrinolysis was due to reduced t-PA release in 40 patients (t-PA group) and to PAI-1 excess in 42 patients (PAI group). No differences in both genotype distribution and allele frequencies were observed between patients and controls. The t-PA:Ag increase after VO (20/0-minute levels ratio adjusted for hematocrit) was considerably higher both in controls and in PAI group patients carrying the I allele than in the DD genotype carriers (II, ID, DD: 3.77+/-0.62, 3.43+/-0.44, 2.06+/-0.32 in controls, and 3.67+/-0.23, 2.80+/-0.50, 1.62+/-0.29 in PAI group, respectively). The difference was significant between the DD and both the ID and II genotypes in controls (p<0.05), and between the DD and II genotypes in PAI-1 group (p<0.05). A slight and nonsignificant trend of association between genotype and t-PA:Ag 20/0 ratio was seen in the t-PA group patients. In conclusion, these data suggest a possible genetic modulation of t-PA-regulated secretion.

Adult↗
PubMed2002

A subject with a novel type I bare lymphocyte syndrome has tapasin deficiency due to deletion of 4 exons by Alu-mediated recombination.

HLA class I expression depends on the formation of a peptide-loading complex composed of class I heavy chain; beta(2)-microglobulin; the transporter associated with antigen processing (TAP); and tapasin, which links TAP to the heavy chain. Defects in TAP result in a class I deficiency called the type I bare lymphocyte syndrome (BLS). In the present study, we examined a subject with a novel type I BLS who does not exhibit apparent TAP abnormalities but who has a tapasin defect. The subject's TAPASIN gene has a 7.4-kilobase deletion between introns 3 and 7; an Alu repeat-mediated unequal homologous recombination may be the cause of the deletion. No tapasin polypeptide was detected in the subject's cells. The cell surface class I expression level in tapasin-deficient cells was markedly reduced but the reduction was not as profound as in TAP-deficient cells. These results suggest that tapasin deficiency is another cause of type I BLS.

Alu Elements↗
PubMed2004

An Alu-mediated 31.5-kb deletion as the cause of factor XI deficiency in 2 unrelated patients.

Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable severity. Inheritance is not completely recessive as heterozygotes may display a distinct, if mild, bleeding tendency. Recent studies have shown the causative mutations of factor XI deficiency, outside the Ashkenazi Jewish population, to be highly heterogeneous. We studied 39 consecutively referred patients with factor XI deficiency to identify the molecular defect. Conventional mutation screening failed to identify a causative mutation in 4 of the 39 patients. Epstein-Barr virus (EBV)-transformed cells from these 4 patients were converted from a diploid to haploid chromosome complement. Subsequent analysis showed that 2 of the patients had a large deletion, which was masked in the heterozygous state by the presence of a normal allele. We report here the first confirmed whole gene deletion as the causative mutation of factor XI deficiency, the result of unequal homologous recombination between flanking Alu repeat sequences.

Alu Elements↗
PubMed2004

The putative tumor suppressor deleted in malignant brain tumors 1 is an estrogen-regulated gene in rodent and primate endometrial epithelium.

Deleted in malignant brain tumors 1 (DMBT1) is a candidate suppressor of malignancies of the brain, lung, gut, and breast. We have been studying gene expression in the uterus in the presence of estrogens and their antagonists. Here, we show that DMBT1 RNA levels are robustly increased by estrogen treatment in the uteri of ovariectomized monkeys and rats. In monkeys, the progestin antagonist mifepristone inhibits estrogen-dependent uterine proliferation. As determined by a microarray experiment and quantitative analysis of RNA levels, mifepristone inhibited estrogenic induction of DMBT1. DMBT1 was not expressed in intact monkeys that were treated with a gonadotropin agonist to suppress steroidogenesis. An in vitro transfection study with human DMBT1 promoter constructs showed that an Alu site approximately 3000 nucleotides upstream of the gene mediates estrogenic regulation. Surprisingly, the estrogen antagonists tamoxifen, raloxifene, and ICI 182,780 also induced gene expression via this Alu site. Rodents represent a more convenient model system for studying uterine biology than monkeys. In rats, uterine DMBT1 RNA levels were dramatically up-regulated by estrogen. Consistent with the transfection study, tamoxifen and raloxifene increased DMBT1 RNA levels in vivo, but ICI 182,780 inhibited an estrogen-induced increase. Immunohistochemical studies showed that DMBT1 is specifically induced in glandular and luminal epithelia of the rat endometrium. Our experiments establish that DMBT1 is an estrogen-responsive gene with a possible role in endometrial proliferation or differentiation, and they have implications for the putative tumor suppressive and mucosal protective functions of DMBT1 in the uterus.

Agglutinins↗
PubMed2004

DNA fingerprints provide a patient-specific breast cancer marker.

BACKGROUND: Detection of systemic breast cancer recurrence is limited by lack of universally expressed tumor cell markers. We hypothesized that a test that detects genetic alterations specific to breast cancer cells of an individual patient would provide a superior cancer marker. METHODS: DNA was extracted from blood, primary tumor, and axillary lymph nodes of 33 breast cancer patients and normal breast tissue of 12 control patients. A patient's genome was scanned by PCR amplification between Alu sequences. A DNA fingerprint of approximately 17-40 bands was produced for comparison between normal blood and sampled tissues. RESULTS: There were 7 stage I, 18 stage II, 7 stage III, and 1 stage IV breast cancer cases; 33 of 33 cancer cases showed DNA fingerprint differences between blood and primary tumor (P <.0001). This test predicted 100% of positive nodes. No false-negatives occurred, and in two cases malignancy was detected in histologically negative nodes. Three of the 12 controls showed a single similar band change. CONCLUSIONS: DNA fingerprinting is a method for detecting and characterizing genetic alterations specific to an individual patient's primary tumor in 100% of cases tested. These specific changes were also identified in 100% of positive nodes, proving the capacity of the test to detect metastases.

Alu Elements↗
PubMed2004

Saccharomyces SRP RNA secondary structures: a conserved S-domain and extended Alu-domain.

The contribution made by the RNA component of signal recognition particle (SRP) to its function in protein targeting is poorly understood. We have generated a complete secondary structure for Saccharomyces cerevisiae SRP RNA, scR1. The structure conforms to that of other eukaryotic SRP RNAs. It is rod-shaped with, at opposite ends, binding sites for proteins required for the SRP functions of signal sequence recognition (S-domain) and translational elongation arrest (Alu-domain). Micrococcal nuclease digestion of purified S. cerevisiae SRP separated the S-domain of the RNA from the Alu-domain as a discrete fragment. The Alu-domain resolved into several stable fragments indicating a compact structure. Comparison of scR1 with SRP RNAs of five yeast species related to S. cerevisiae revealed the S-domain to be the most conserved region of the RNA. Extending data from nuclease digestion with phylogenetic comparison, we built the secondary structure model for scR1. The Alu-domain contains large extensions, including a sequence with hallmarks of an expansion segment. Evolutionarily conserved bases are placed in the Alu- and S-domains as in other SRP RNAs, the exception being an unusual GU(4)A loop closing the helix onto which the signal sequence binding Srp54p assembles (domain IV). Surprisingly, several mutations within the predicted Srp54p binding site failed to disrupt SRP function in vivo. However, the strength of the Srp54p-scR1 and, to a lesser extent, Sec65p-scR1 interaction was decreased in these mutant particles. The availability of a secondary structure for scR1 will facilitate interpretation of data from genetic analysis of the RNA.

Alu Elements↗
PubMed2002

Lack of association between Y chromosome Alu insertion polymorphism and hypertension.

There is an inherited paternal predisposition to hypertension. Y chromosome alphoid satellite variation was recently reported to be linked to diastolic blood pressure. To determine whether there is also a Y chromosome marker linked to hypertension, we investigated the prevalence of the Y chromosome Alu insertion polymorphism (YAP) at DYS287 and its association with hypertension in the Aomori population in the northern area of Honshu Island, Japan. YAP was present in 98 of 285 male residents and absent in the rest. The YAP prevalence in the present study would appear to suggest that the present study population represents the general male population in central Japan. Within the study population, there were 110 hypertensive subjects and 104 normotensive subjects. YAP frequency in the hypertensive subjects was not different from that in the normotensive subjects. These results suggest that the YAP is not likely to be a genetic-susceptibility factor for hypertension in the Aomori population.

Adult↗
PubMed2002

Alu-repeat polymorphism in the gene coding for tissue-type plasminogen activator and the risk of hypertension in a Chinese Han population.

Accumulating data support an association between hypertension and impaired fibrinolytic potential abnormalities in endogenous fibrinolysis. The present study examined whether there was an association between essential hypertension and either a polymorphism in the gene coding for t-PA or the plasma concentration of t-PA antigen. Chinese hypertensive subjects (n = 126) and normotensive controls (n = 102; sex- and age-matched with hypertensives) were recruited from among the outpatients of FuWai Hospital. The distributions of the II, ID, and DD genotypes of the t-PA gene in hypertensive patients (0.15, 0.49, 0.36) were similar to those in control subjects (0.11, 0.51, 0.38; p = 0.626). No significant difference in overall allele frequencies was found between the hypertension and control groups (p = 0.656). The allelic frequencies were in Hardy-Weinberg equilibrium. There was no evidence of an association between the level of t-PA antigen and risk of hypertension. Thus, in this case control study, neither the presence of the insertion allele of the Alu-repeat polymorphism of the t-PA nor the level of t-PA antigen were associated with the risk of essential hypertension.

Aged↗
PubMed2003

Angiotensin-converting enzyme gene (ACE) insertion/deletion polymorphism in Mexican populations.

The angiotensin-converting enzyme gene (ACE) insertion/deletion polymorphism was determined in 211 Mexican healthy individuals belonging to different Mexican ethnic groups (98 Mestizos, 64 Teenek, and 49 Nahuas). ACE polymorphism differed among Mexicans with a high frequency of the D allele and the D/D genotype in Mexican Mestizos. The D/D genotype was absent in Teenek and present in only one Nahua individual (2.0%). When comparisons were made, we observed that Caucasian, African, and Asian populations presented the highest frequencies of the D allele, whereas Amerindian (Teenek and Pima) and Australian Aboriginals showed the highest frequencies of the I allele. The distribution of I/D genotype was heterogeneous in all populations: Australian Aboriginals presented the lowest frequency (4.9%), whereas Nahuas presented the highest (73.4%). The present study shows the frequencies of a polymorphism not analyzed previously in Mexican populations and establishes that this polymorphism distinguishes the Amerindian populations of other groups. On the other hand, since ACE alleles have been associated with genetic susceptibility to developing cardiovascular diseases and hypertension, knowledge of the distribution of these alleles could help to define the true significance of ACE polymorphism as a genetic susceptibility marker in the Amerindian populations.

Alu Elements↗
PubMed2003

Insertion/deletion polymorphisms in tribal populations of southern India and their possible evolutionary implications.

India has the unique distinction of having perhaps the largest diversities, both biological and cultural. The Nilgiri Hills of southern India, a home for several tribal pockets representing different genetic isolates, provides a genetic wealth to understand human evolution. We have analyzed eight widely distributed polymorphic insertion/deletion loci (AluAPO, AluACE, AluDI, AluPLAT, AluPV92, AluFXIIIB, CD4 del and mtNUC) in 250 unrelated individuals from five tribal populations (Badaga, Irula, Kota, Kurumba, and Toda). All loci were highly polymorphic except the CD4 del locus, at which the deletion allele was fixed in Kotas and Kurumbas. The levels of average heterozygosities were found to be high in all the populations. In most populations, they were also higher than those predicted by the island model of population structure. The gene diversity (GST = 8.3%) was found to be higher than that in populations of most global regions with the exception of Africa. It is clear from the present study that drift effects could have accentuated the process of genetic differentiation of the tribal populations. The possibility of an early demographic expansion of modern humans within south India also cannot be ruled out.

Alu Elements↗