Concurrent positive association between pathological gambling and functional DNA polymorphisms at the MAO-A and the 5-HT transporter genes.
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Carrier Proteins↗
Biomedical subjects
I Pérez de Castro
Publications and source records attributed to I Pérez de Castro.
Psychiatric comorbidity in pathological gamblers seeking treatment.
OBJECTIVE: The authors' goal was to determine the frequency of psychiatric comorbidity among treatment-seeking pathological gamblers, compare the severity of gambling and psychological problems in gamblers with and without comorbid disorders, and investigate differences between gamblers with and without comorbid disorders in the dopamine D(2) receptor gene (DRD(2)). METHOD: Sixty-nine pathological gamblers who consecutively applied to a specialized outpatient treatment program were evaluated with structured interviews, self-report questionnaires, and psychological scales and were genotyped for a DRD(2) polymorphism. RESULTS: A comorbid psychiatric disorder was present in 43 (62.3%) of the gamblers. The most frequent diagnoses were personality disorders (N=29 [42.0%]), alcohol abuse or dependence (N=23 [33.3%]), and adjustment disorders (N=12 [17.4%]). Gamblers with comorbid psychiatric disorders had gambling scores and psychological scale scores indicating greater severity of gambling and psychopathology. Significant differences in DRD(2) allele distribution were found in gamblers with and without comorbid disorders. CONCLUSIONS: Psychiatric comorbidity is common among pathological gamblers and is associated with greater severity of clinical problems. The DRD(2) gene could be a liability genetic factor for psychiatric comorbidity in pathological gambling.
Comorbidity↗
Characterization of the murine p19(ARF) promoter CpG island and its methylation pattern in primary lymphomas.
The INK4a/ARF locus encodes two different proteins involved in cell cycle control. Both molecules, p16(INK4a) and p19(ARF), inhibit cell cycle progression and have been shown to act as tumor suppressors in a variety of models. Their expression is controlled by separate promoters responding to different stimuli and they therefore show independent transcriptional regulation. We have cloned and characterized a 2.5 kb region upstream of the murine p19(ARF) gene to determine the role of DNA methylation in suppressing p19(ARF) transcription in a wide panel of murine primary T cell lymphomas. This region contains a DNA fragment with the characteristics of a CpG island similar to those described for the murine p16(INK4a) and p15(INK4b) genes. Expression of p19(ARF) is decreased in a significant number (20%) of the murine lymphomas analyzed. Overexpression of the p19(ARF) transcript is also frequent, suggesting alterations in molecules of the retinoblastoma or p53 pathways that are involved in p19(ARF) regulation. Although hypermethylation of the INK4a and INK4b promoters is frequently involved in murine lymphomas, the p19(ARF) CpG island is infrequently methylated in the murine primary lymphomas studied in this work. Since loss of p19(ARF) expression cannot be explained as the result of homozygous deletions or hypermethylation of the ARF gene, other regulatory mechanisms seem to be altered in these malignancies.
Animals↗
Hypermethylation of the cell cycle inhibitor p15INK4b 3'-untranslated region interferes with its transcriptional regulation in primary lymphomas.
The cyclin-dependent kinase inhibitor p15INK4b has been shown to be involved in human and rodent tumors and seems to act as a tumor suppressor gene in hematological malignancies. Alterations of this gene in tumors include mainly homozygous deletions and hypermethylation of the CpG island in the promoter region. In this work, we describe a new area sensitive to methylation in the 3' untranslated region (UTR) of the murine p15INK4b gene. This region shows different levels of methylation depending on the tissues, being relatively highly methylated in brain and gut, and weakly methylated in liver, spleen or thymus. DNA methylation and expression is similar in both maternal and paternal alleles indicating no imprinting effect. Although methylation of the p15INK4b 3'-UTR is low in normal thymus, increased levels (up to 100%) of specific methylation in this region are found in up to 30% of radiation- or carcinogen-induced thymic lymphomas, correlating with decreased gene expression. Hypermethylation of the p15INK4b 3'-UTR frequently occurs in tumors with loss of heterozygosity (LOH) but without methylation of the promoter CpG island or intragenic mutations. Furthermore, in vitro CpG methylation of the 3'-UTR produces reduced levels of a luciferase reporter in cultured cells. Methylation of two CpG sites in a 120 bp region is sufficient to interfere with transcription of the reporter gene. These data suggest that although the levels of p15INK4b in normal tissues can be mainly determined by promoter regulatory elements, strong hypermethylation of the 3'-UTR can interfere with transcription. Thus, hypermethylation of the 3'-UTR may explain the lack of p15INK4b gene expression in a subset of tumors with no promoter methylation and could be a new alternative mechanism for tumor suppressor gene inactivation in tumorigenesis.
3' Untranslated Regions↗
Genetic contribution to pathological gambling: possible association between a functional DNA polymorphism at the serotonin transporter gene (5-HTT) and affected men.
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Adult↗
A new candidate site for a tumor suppressor gene involved in mouse thymic lymphomagenesis is located on the distal part of chromosome 4.
In a previous work we provided preliminary evidence of the existence of a putative tumor suppressor gene region on the distal part of chromosome 4 in gamma-radiation-induced T-cell lymphomas of (C57BL/6J x RF/J) F1 hybrid mice. This region, named as TLSR2 (Thymic Lymphoma Suppressor Region 2), was located centered at D4Mit54. A more detailed allelotype analysis in the mentioned tumors with new informative microsatellites on distal chromosome 4 region, as well as in thymic lymphomas induced with gamma-rays in F1 hybrids generated from reciprocal crosses between the strains C57BL/6J and BALB/cJ, and having in mind the new map position of D4Mit205b, allowed us to confirm the existence of TLSR2 and to define it more precisely as centered at D4Mit205b. In addition, we identified a new candidate region, named as TLSR3 (Thymic Lymphoma Suppressor Region 3), located between the Mom-1 locus and D4Mit68, as the site of another putative tumor suppressor region involved in thymic lymphomagenesis.
Animals↗
An AC-repeat adjacent to mouse Cdkn2B allows the detection of specific allelic losses in the p15INK4b and p16INK4a tumor suppressor genes.
The cyclin-dependent kinase inhibitors p15INK4b and p16INK4a are involved in the development of a wide range of human and murine tumors. These tumor suppressor genes are inactivated by deletions frequently associated to point mutations in the coding regions or hypermethylation of their promoters. In this work, we describe a simple-sequence length polymorphism located in mouse Chromosome (Chr) 4, between the Cdkn2B (p15INK4b) and Cdkn2A (p16INK4a) genes, only 700 bp downstream of the Cdkn2B locus. This DNA region was analyzed in different inbred strains showing a variable AC-repetitive DNA sequence. We used this microsatellite to detect loss of heterozygosity of the Cdkn2A and Cdkn2B loci in gamma-irradiation-induced thymic lymphomas of C57BL/6J x RF/J F1 hybrids. Using this specific marker, we were able to locate additional allelic losses not detected by other microsatellites. Since the allelic losses can be detected by a simple PCR amplification, this AC-repetitive sequence is specially useful as a genetic marker for these Cdkn2 genes and specifically for the p15INK4b cell cycle inhibitor.
Alleles↗
Frequent allelic losses of 9p21 markers and low incidence of mutations at p16(CDKN2) gene in non-Hodgkin lymphomas of B-cell lineage.
We present an allelotype analysis of 35 cases of non-Hodgkin lymphomas and normal pairs using four microsatellite markers that flank the region occupied by the CDKN2 gene locus at 9p21. Frequent allelic losses (LOH) were detected in B-cell lineage NHLs, including Burkitt lymphoma (33.3% of total, if we only consider high grade tumors). In five of these tumors LOH did not include the CDKN2 gene. Mutational analysis of exon 1 and 2 of CDKN2 (SSGP and sequencing of abnormal bands) revealed a nonsense mutation (Arg72Ter) in one tumor (case 10), where the second hit of the Knudson's model consisted of the elimination of the wild type allele. In view of these results, the hypothesis of two different candidate tumor suppressor gene regions around the CDKN2 locus remains an intriguing possibility.
Alleles↗
Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas.
A wide panel of murine induced T-cell lymphomas have been analysed for p16INK4a or p15INK4b alterations. Only one gamma-radiation-induced lymphoma showed p16INK4a homozygous deletion and no other intragenic mutations were found in these INK4 genes. However, de novo methylation of the 5' CpG islands of the murine p15INK4b and p16INK4a genes was found to be highly frequent. While p16INK4a hypermethylation was found in 36% of the neutron-radiation-induced lymphomas and 15% of the gamma-radiation-induced lymphomas, de novo methylation of p15INK4b occurs in 88% and 42% of these tumors respectively, correlating with deficient expression of the corresponding mRNA and allelic losses in the p15INK4b and p16INK4a chromosome location. These data represent, to our knowledge, the first report on the significant involvement of hypermethylation of these INK4 genes in murine primary tumors. Moreover, they show the importance of allelic losses and CpG island methylation of p15INK4b gene inactivation and support a tumor suppressor role for p15INK4b in T-cell lymphomas independent of p16INK4a.
Animals↗
Instability of the D4Mit12 microsatellite marker in C57BL/6J x BALB/cJF1 hybrid mice is independent of the tumor phenotype.
We examined the stability of different types of DNA microsatellite markers in gamma-radiation-induced thymic lymphomas as well as normal, nontumorous tissues of F1 hybrid mice derived from the parental strains C57BL/6J, RF/J, and BALB/cJ. Surprisingly, the D4Mit12 microsatellite showed genomic instability in a significant fraction of DNAs of the (C57BL/6J x BALB/cJ) F1 hybrids with independence of the tumor phenotype. This instability was not found in the reciprocal F1 DNAs, in DNAs of the parental strains, or in DNAs of (C57BL/6J x RF/J) F1 hybrid mice. These results suggest that the instability of the D4Mit 12 microsatellite is dependent on its repeat length, the genetic background of F1 hybrids, and the maternal origin of the C57BL/6J allele.
Animals↗
Genetic association study between pathological gambling and a functional DNA polymorphism at the D4 receptor gene.
A Spanish sample consisting of 68 Caucasian pathological gambling patients (47 males and 21 females) and 68 unaffected controls were screened by the molecular analysis of a functional DNA polymorphism in the locus for the D4 dopamine receptor gene. Our results are consistent with the existence of a significant association between genetic variants at a DRD4 gene polymorphism and pathological gambling (chi 2 = 11.82; P = 0.037). This association seems to be sex-influenced, since there was no significant association when only males were considered (chi 2 = 9.45; P = 0.09), but there was a more significant association if we only considered female subjects (chi 2 = 8.73; P = 0.033). Individuals with the longest allele (D7) were the most frequent in affected females (chi 2 = 4.50; P = 0.033). This work provides a new evidence of the implication of the dopaminergic reward pathways, now through the involvement of DRD4, in the aetiology of this impulsive disorder.
Alleles↗
Allelic losses on chromosome 4 suggest the existence of a candidate tumor suppressor gene region of about 0.6 cM in gamma-radiation-induced mouse primary thymic lymphomas.
Mouse chromosome 4 was investigated to assess the involvement of tumor suppressor genes in primary thymic lymphomas induced by gamma-irradiation. PCR analysis using microsatellite DNA polymorphic markers was performed in F1 animals generated from a cross between the strains C57BL/6J and RF/J. Microsatellite markers were selected with focus on chromosome 4 around the region containing the interferon alpha gene cluster (D4Mit17, D4Wsm1, D4Mit9, and D4Mit205 and a more distal region (D4Mit12, D4Mit54, and D4Mit13). Allelic losses were detected in 21/47 (44.7%) gamma-radiation-induced thymic lymphomas. Analysis of markers located on six other chromosomes as well as on the proximal region of chromosome 4 illustrates the specificity of the occurrences of LOH appearing on the former markers. This analysis clearly suggests the existence of a candidate tumor suppressor gene region on mouse chromosome 4 of about 0.6 cM between the markers D4Wsm1 and D4Mit9 (TLSR1, Thymic Lymphoma Suppressor Region 1). In addition, another more distal region centered at the marker D4Mit54 could be also exist (TLSR2). In most tumors, allelic losses on these chromosome regions involved the paternal RF/J allele (19 of 20).
Alleles↗
No association between particular DRD3 and DAT gene polymorphisms and manic-depressive illness in a Spanish sample.
We have carried out an association study of a polymorphism in the 3'UTR of the dopamine transporter gene (DAT) and a polymorphism in the coding region of the D3 receptor gene (DRD3) in Spanish patients with manic depression and in controls. No significant differences in allelic and genotypic frequencies of either of these polymorphisms was found in patients compared with controls.
Bipolar Disorder↗
Familial cosegregation of manic-depressive illness and a form of hereditary cerebellar ataxia.
We report on a Spanish family with cooccurrence of manic-depression and a form of hereditary cerebellar ataxia. All affected individuals in the second generation showed cerebellar ataxia and manic-depression simultaneously. Since anticipation has been described in both disorders and the pattern of segregation may be autosomal as well as X-linked, we have searched for a possible involvement of two candidate genes which are located either on an autosome (SCA1) or on the X-chromosome (GABRA3). We concluded that expansion of trinucleotide repeats at SCA1 gene cannot be considered as a disease-causing mutation, and this gene should be initially discarded.
Adolescent↗
A weak association between TH and DRD2 genes and bipolar affective disorder in a Spanish sample.
Genetic factors play an important role in the aetiology of bipolar affective disorder (BP). So far, results of linkage studies have been largely disappointing. We have searched for a possible association between polymorphic DNA markers of two candidate genes (tyrosine hydroxylase, TH; dopamine D2 receptor gene, DRD2) and BP in a population from central Spain. Our results are consistent with the existence of a weak association between these two genes and BP, in such a way that TH and DRD2 could be considered as minor genes contributing to susceptibility.
Adult↗
Eight new polymorphic microsatellites in mouse gene loci.
Eight mouse gene loci (Atp1b2, Epo, Kit, Krt2, Mor1, Ren1, Pdgfb, and Wnt1) that contain unidentified microsatellites were selected to detect simple sequence-length polymorphisms on genomic DNAs from two laboratory strains (C57BL/6J and RF/J) and strains recently derived from the Mus musculus species complex (CAST/Ei, MOLF/Ei, CZECH II, and M. m. domesticus) and from M. spretus (SPRET/Ei). All microsatellite DNA sequences varied in size among some of the seven mouse strains tested. These new polymorphisms might be useful in the search for tumor suppressor genes involved in specific cancers.
Animals↗
No association between dopamine D4 receptor polymorphism and manic depressive illness.
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Adult↗
[Inter-consultations and complementary tests in a health center].
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Ambulatory Care Facilities↗