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Results for “DNA Repeat Expansion”

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PubMed2006

Association between DRD4 gene and performance of children with ADHD in a test of sustained attention.

BACKGROUND: The adoption of neuropsychological tests as endophenotypic measures can provide an increased sensitivity to specific dimensions of attention-deficit/hyperactivity disorder (ADHD). METHODS: The association between a variable number of tandem repeats polymorphism at the dopamine D4 receptor gene (DRD4) and the performance of children and adolescents with ADHD in a continuous performance test (CPT) was evaluated. The sample comprised 90 clinically referred children and adolescents with ADHD. Errors of omission and commission in the CPT were computed and the number of 48-base pairs tandem repeats in the exon III of DRD4 was assessed. RESULTS: The presence of a 7-repeat allele was associated with more errors of commission and the homozygosity of the 4-repeat allele was related to fewer errors of commission and omission even after adjusting for age. CONCLUSIONS: These findings bring further evidence on the role of DRD4 polymorphisms on the performance in sustained attention tasks among children and adolescents with ADHD diagnosis.

Adolescent↗
PubMed2006

Novelty seeking involved in mediating the association between the dopamine D4 receptor gene exon III polymorphism and heavy drinking in male adolescents: results from a high-risk community sample.

BACKGROUND: Previous research suggests that personality traits, particularly novelty seeking (NS), increase the risk of substance abuse. One possible explanation to account for this association relates to common genetic factors. The aim of this study was to examine whether allelic variants of the dopamine D4 receptor gene (DRD4) are associated with alcohol use in adolescents and to determine the extent to which these links are mediated by NS. METHODS: Three hundred three adolescents (144 male participants, 159 female participants, approximately 15 years old) from a high-risk community sample completed self-report questionnaires measuring alcohol intake and temperament (Junior Temperament and Character Inventory [JTCI]). DNA was genotyped for the DRD4 exon III polymorphism. RESULTS: Male participants carrying the 7-repeat allele of DRD4 drank higher maximum amounts of alcohol per occasion and had greater lifetime rates of heavy drinking than male participants without this allele. Higher levels of NS were associated with higher alcohol intake in both genders. Multiple regression analyses support the role of NS in mediating the relationship between DRD4 and heavy drinking in male adolescents but not in female adolescents. CONCLUSIONS: These findings extend previous work highlighting the significance of personality traits as a mediating factor between genetic susceptibility and substance use during the period of early experimental use.

Adolescent↗
PubMed2006

Expanded simple tandem repeat (ESTR) mutation induction in the male germline: lessons learned from lab mice.

Expanded simple tandem repeat (ESTR) DNA loci that are unstable in the germline have provided the most sensitive tool ever developed for investigating low-dose heritable mutation induction in laboratory mice. Ionizing radiation exposures have shown that ESTR mutations occur mainly in pre-meiotic spermatogonia and stem cells. The average spermatogonial doubling dose is 0.62-0.69 Gy for low LET, and 0.18-0.34 Gy for high LET radiation. Chemical alkylating agents also cause significant ESTR mutation induction in pre-meiotic spermatogonia and stem cells, but are much less effective per unit dose than radiation. ESTR mutation induction efficiency is maximal at low doses of radiation or chemical mutagens, and may decrease at higher dose ranges. DNA repair deficient mice (SCID and PARP-1) with elevated levels of single and double-strand DNA breaks have spontaneously elevated ESTR mutation frequencies, and surprisingly do not show additional ESTR mutation induction following irradiation. In contrast, ESTR mutation induction in p53 knock-outs is indistinguishable from that of wild-type mice. Studies of sentinel mice exposed in situ to ambient air pollution showed elevated ESTR mutation frequencies in males exposed to high levels of particulate matter. These studies highlight the application of the ESTR assay for assessing environmental hazards under real-world conditions. All ESTR studies to date have shown untargeted mutations that occur at much higher frequencies than predicted. The mechanism of this untargeted mutation induction is unknown, and must be elucidated before we can fully understand the biological significance of ESTR mutations, or use these markers for formal risk assessment. Future studies should focus on the mechanism of ESTR mutation induction, refining dose responses, and developing ESTR markers for other animal species.

Animals↗
PubMed2006

A Drosophila ortholog of the human MRJ modulates polyglutamine toxicity and aggregation.

In the Drosophila eye, proteins with an expanded polyglutamine (polyQ) tract form nuclear and cytoplasmic inclusions and produce cytotoxicity, demonstrated as loss of eye pigmentation and structural integrity. An EP P-element that suppressed the loss of eye pigmentation was inserted 9.7 kb upstream of dmrj, a gene that encodes an ortholog of a brain-enriched cochaperone, the human MRJ (mammalian relative of DnaJ). Despite the large distance between them, quantitative polymerase chain reaction indicated that the EP could overexpress dmrj. In the retina and other neurons, transgenic dMRJ suppressed polyQ toxicity and colocalized with its inclusions. In the photoreceptors, expression of another suppressor with a J domain, dHDJ1, but not dMRJ, prior to expression of expanded polyQs dramatically promoted cytoplasmic aggregation. However, both proteins increased the level of detergent-soluble, monomeric polyQ-expanded proteins. These findings exemplify the functional similarities and differences between J domain proteins in suppressing polyQ toxicity.

Amino Acid Sequence↗
PubMed2004

Cerebellum development and schizophrenia: an association study of the human homeogene Engrailed 2.

Epidemiological data and family studies in schizophrenia show that genetic factors contribute to the vulnerability to this disorder. The homeogene Engrailed 2 (EN2) is specifically involved in patterning the region that gives rise to the cerebellum and controls the plasticity of midbrain dopaminergic neurons. We carried out an association study for a CA repeat polymorphism located in the 3' region of the homeogene EN2. The subjects consisted of 165 patients with schizophrenia and 97 controls matched for age and ethnicity from a French Caucasian population. We found no significant association of schizophrenia with this bi-nucleotide repeat polymorphism of the EN2 gene.

Adult↗
PubMed2006

A dopamine transporter polymorphism is a risk factor for borderline personality disorder in depressed patients.

BACKGROUND: Borderline personality disorder (BPD) is often co-morbid with major depression and may complicate its treatment. We were interested in differences in genetic and developmental risk factors between depressed patients with or without a co-morbid BPD. METHOD: Out-patients with major depressive disorder were recruited for two treatment trials. Assessment of depressed patients included the assessment of personality disorders, developmental risk factors and DNA samples for genetic analyses. RESULTS: In each study there was a significant association between the 9-repeat allele of the dopamine transporter (DAT1) and BPD, with odds ratios (OR) > 3 and p < or = 0.02. This association remained significant when developmental risk factors for BPD (childhood abuse and neglect and borderline temperament) were also included in the analyses. The OR was even larger in the depressed patients aged > or = 35 years (OR 9.31, p = 0.005). CONCLUSION: This replicated association in depressed patients between the 9-repeat allele of DAT1 and BPD may provide clues to understanding the neurobiology of BPD. The finding that the association is larger in the older depressed patients, suggests that the 9-repeat allele may be associated with a poorer prognosis BPD, rather than a young adult limited variant of BPD.

Adult↗
PubMed2006

Case report of Haddad syndrome in a newborn: congenital central hypoventilation syndrome and Hirschsprung's disease.

Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by failure of automatic control of breathing. Diagnosis is made by exclusion of other causes of hypoventilation. Genetic etiology is strongly suspected. Other autonomic nervous system dysfunctions, tumors of neural crest origin and Hirschsprung's disease are often found in affected children. Association with Hirschsprung's disease is known as Haddad syndrome. We present a newborn with respiratory distress since birth and Hirschprung's disease subsequently diagnosed with Haddad syndrome.

Carbon Dioxide↗
PubMed2005

Ataxin-7 can export from the nucleus via a conserved exportin-dependent signal.

Spinocerebellar ataxia type 7 is a progressive neurodegenerative disorder caused by a CAG DNA triplet repeat expansion leading to an expanded polyglutamine tract in the ataxin-7 protein. Ataxin-7 appears to be a transcription factor and a component of the STAGA transcription coactivator complex. Here, using live cell imaging and inverted fluorescence recovery after photobleaching, we demonstrate that ataxin-7 has the ability to export from the nucleus via the CRM-1/exportin pathway and that ataxin-7 contains a classic leucine-type nuclear export signal (NES). We have precisely defined the location of this NES in ataxin-7 and found it to be fully conserved in all vertebrate species. Polyglutamine expansion was seen to reduce the nuclear export rate of mutant ataxin-7 relative to wild-type ataxin-7. Subtle point mutation of the NES in polyglutamine expanded ataxin-7 increased toxicity in primary cerebellar neurons in a polyglutamine length-dependent manner in the context of full-length ataxin-7. Our results add ataxin-7 to a growing list of polyglutamine disease proteins that are capable of nuclear shuttling, and we define an activity of ataxin-7 in the STAGA complex of trafficking between the nucleus and cytoplasm.

3T3 Cells↗
PubMed2004

The fragile-X premutation: a maturing perspective.

Carriers of premutation alleles (55-200 CGG repeats) of the fragile-X mental retardation 1 (FMR1) gene are often regarded as being clinically uninvolved. However, it is now apparent that such individuals can present with one (or more) of three distinct clinical disorders: mild cognitive and/or behavioral deficits on the fragile-X spectrum; premature ovarian failure; and a newly described, neurodegenerative disorder of older adult carriers, fragile-X-associated tremor/ataxia syndrome (FXTAS). Awareness of these clinical presentations is important for proper diagnosis and therapeutic intervention, not only among families with known cases of fragile-X syndrome but also more broadly for adults with tremor, gait ataxia, and parkinsonism who are seen in movement-disorders clinics.

Chromosomes, Human, X↗
PubMed2004

Are expanded polyglutamine proteins a proteasome substrate?

Protein degradation is essential to preserve cellular homeostasis since it is an important step in a variety of cellular processes. Among the intracellular proteolytic systems, the proteasome is considered to play a major role in basal protein turnover, that is, degradation of abnormal/damaged proteins. The accumulation of protein aggregates as well as various components of the ubiquitin/proteasome system raises the possibility that an impaired proteasome function may be a causal factor in the cellular degeneration that occurs in neurodegenerative disorders caused by expanded polyglutamine repeats.

Animals↗
PubMed2005

HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism.

The 'expanded' HD CAG repeat that causes Huntington's disease (HD) encodes a polyglutamine tract in huntingtin, which first targets the death of medium-sized spiny striatal neurons. Mitochondrial energetics, related to N-methyl-d-aspartate (NMDA) Ca2+-signaling, has long been implicated in this neuronal specificity, implying an integral role for huntingtin in mitochondrial energy metabolism. As a genetic test of this hypothesis, we have looked for a relationship between the length of the HD CAG repeat, expressed in endogenous huntingtin, and mitochondrial ATP production. In STHdhQ111 knock-in striatal cells, a juvenile onset HD CAG repeat was associated with low mitochondrial ATP and decreased mitochondrial ADP-uptake. This metabolic inhibition was associated with enhanced Ca2+-influx through NMDA receptors, which when blocked resulted in increased cellular [ATP/ADP]. We then evaluated [ATP/ADP] in 40 human lymphoblastoid cell lines, bearing non-HD CAG lengths (9-34 units) or HD-causing alleles (35-70 units). This analysis revealed an inverse association with the longer of the two allelic HD CAG repeats in both the non-HD and HD ranges. Thus, the polyglutamine tract in huntingtin appears to regulate mitochondrial ADP-phosphorylation in a Ca2+-dependent process that fulfills the genetic criteria for the HD trigger of pathogenesis, and it thereby determines a fundamental biological parameter--cellular energy status, which may contribute to the exquisite vulnerability of striatal neurons in HD. Moreover, the evidence that this polymorphism can determine energy status in the non-HD range suggests that it should be tested as a potential physiological modifier in both health and disease.

Adenosine Diphosphate↗
PubMed1998

Expansion and contraction of ribosomal DNA repeats in Saccharomyces cerevisiae: requirement of replication fork blocking (Fob1) protein and the role of RNA polymerase I.

Saccharomyces cerevisiae carries approximately 150 copies of rDNA in tandem repeats. It was found that the absence of an essential subunit of RNA polymerase I (Pol I) in rpa135 deletion mutants triggers a gradual decrease in rDNA repeat number to about one-half the normal level. Reintroduction of the missing RPA135 gene induced a gradual increase in repeat number back to the normal level. Gene FOB1 was shown to be essential for both the decrease and increase of rDNA repeats. FOB1 was shown previously to be required for replication fork blocking (RFB) activity at RFB site in rDNA and for recombination hot-spot (HOT1) activity. Thus, DNA replication fork blockage appears to stimulate recombination and play an essential role in rDNA expansion/contraction and sequence homogenization, and possibly, in the instability of repeated sequences in general. RNA Pol I, on the other hand, appears to control repeat numbers, perhaps by stabilizing rDNA with the normal repeat numbers as a stable nucleolar structure.

Blotting, Southern↗
PubMed2004

Flap endonuclease 1: a central component of DNA metabolism.

One strand of cellular DNA is generated as RNA-initiated discontinuous segments called Okazaki fragments that later are joined. The RNA terminated region is displaced into a 5' single-stranded flap, which is removed by the structure-specific flap endonuclease 1 (FEN1), leaving a nick for ligation. Similarly, in long-patch base excision repair, a damaged nucleotide is displaced into a flap and removed by FEN1. FEN1 is a genome stabilization factor that prevents flaps from equilibrating into structures that lead to duplications and deletions. As an endonuclease, FEN1 enters the flap from the 5' end and then tracks to cleave the flap base. Cleavage is oriented by the formation of a double flap. Analyses of FEN1 crystal structures suggest mechanisms for tracking and cleavage. Some flaps can form self-annealed and template bubble structures that interfere with FEN1. FEN1 interacts with other nucleases and helicases that allow it to act efficiently on structured flaps. Genetic and biochemical analyses continue to reveal many roles of FEN1.

Animals↗
PubMed2004

Control of radiosensitivity of F9 mouse teratocarcinoma cells by regulation of histone H2AX gene expression using a tetracycline turn-off system.

The mouse histone H2AX has unique COOH-terminal serine residues that are phosphorylated in response to double-strand DNA breaks introduced by ionizing radiation. This suggests that H2AX acts to maintain genomic stability. We constructed a tetracycline (tet)-directed turn-off vector and integrated it into F9 mouse teratocarcinoma cells by homologous recombination. In homozygously recombined cells, expression of the histone H2AX gene was repressed to 0.02% of the expression observed in wild-type cells by the addition of doxycycline, an analog of tet. Sensitivity of cells with repressed H2AX expression to X-irradiation was increased 1.95x, indicating that DNA repair was impaired by repression of H2AX. When we s.c. injected tet-regulated F9 cells into the flanks of mice, tumor growth was slightly suppressed by X-irradiation in H2AX-repressed tumors, whereas without X-irradiation, tumor growth did not differ by H2AX status. Thus, H2AX might be a potential molecular target for sensitizing cancer cells to radiotherapy to minimize required irradiation doses.

Animals↗
PubMed2004

Signal transducer and activator of transcription 6 haplotypes and asthma in the Indian population.

In this paper, we report for the first time the results of an investigation on the association of signal transducer and activator of transcription 6 (STAT6) with asthma in the Indian population. A novel polymorphic CA-repeat in the proximal promoter region [R1] and a previously identified CA-repeat in the 5'-untranslated region [R3] were genotyped, and haplotypes [R1_R3] were generated using PHASE software. The 16 repeat allele at the R1 locus was positively associated (P = 0.01) with asthma. The 15 and 16 repeat alleles at the R3 locus were positively (P < 10(-4)) and negatively (P < 10(-5)) associated with asthma, respectively. Further, the 17_15 (P = 0.0031) and 16_15 (P = 0.001) haplotypes were found to be positively associated with asthma, whereas 17_14, 24_16, and 23_16 were negatively associated (P < 10(-5)). It appears that the R3 and R1 loci together play a bigger role in asthma than either of them alone, and the R3 locus has a larger effect than the R1 locus. Although alleles at the R1 locus appeared to be associated with total serum immunoglobulin E level, the genotypes showed no association, and the R3 locus showed no effect. As no exonic variants of STAT6 are known as yet, repeat polymorphisms in the regulatory regions and their haplotypes could be important in deciphering the genetic role of STAT6 in asthma and atopy.

Adult↗
PubMed2006

Clinical implications of FLT3 mutations in pediatric AML.

Activating mutations of the FLT3 gene occur because of an internal tandem duplication of the juxta-membrane domain (FLT3/ITD) or point mutation of the activation loop domain (FLT3/ALM). The presence of FLT3 mutations as well as the allelic ratio of FLT3/ITD (ITD-AR, mutant-wild type ratio) may have prognostic significance. FLT3 mutation status of 630 children with de novo acute myeloid leukemia (AML) treated on CCG-2941 and -2961 was determined, and ITD-AR was calculated for patients with FLT3/ITD. Clinical characteristics and outcomes for patients with FLT3/ALM and FLT3/ITD at varying ITD-ARs was determined and compared with those without FLT3 mutations (FLT3/WT). FLT3/ITD and FLT3/ALM were detected in 77 (12%) and 42 (6.7%) of the patients. Progression-free survival (PFS) was similar in patients with FLT3/ALM and FLT3/WT (51% versus 55%, P = .862). In contrast, PFS at 4 years from study entry for patients with FLT3/ITD was inferior to that of patients with FLT3/WT (31% versus 55%, P < .001). PFS decreased with increasing FLT3/ITD-AR (P < .001), and those with ITD-AR greater than 0.4 had a significantly worse PFS than those with lower ITD-AR (16% versus 72%, P = .001) or with FLT3/WT (55%, P < .001). ITD-AR defines the prognostic significance in FLT3/ITD-positive AML, and ITD-AR greater than 0.4 is a significant and independent prognostic factor for relapse in pediatric AML.

Adolescent↗