Evidence for a new Graves disease susceptibility locus at chromosome 18q21.
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Graves disease (GD) is a common autoimmune thyroid disorder that is inherited as a complex multigenic trait. By using a single microsatellite marker at each locus, we screened the type 1 diabetes loci IDDM4, IDDM5, IDDM6, IDDM8, and IDDM10 and the fucosyltransferase-2 locus for linkage in sib pairs with GD. This showed a two-point nonparametric linkage (NPL) score of 1.57 (P=.06) at the IDDM6 marker D18S41, but NPL scores were <1.0 at the other five loci. Thus, the investigation of the IDDM6 locus was extended by genotyping 11 microsatellite markers spanning 48 cM across chromosome 18q12-q22 in 81 sib pairs affected with autoimmune thyroid disease (AITD). Multipoint analysis, designating all AITD sib pairs as affected, showed a peak NPL score of 3.46 (P=.0003), at the marker D18S487. Designation of only GD cases as affected (74 sib pairs) showed a peak NPL score of 3.09 (P=.001). Linkage to this region has been demonstrated in type 1 diabetes (IDDM6), rheumatoid arthritis, and systemic lupus erythematosus, which suggests that this locus may have a role in several forms of autoimmunity. (+info)
Examination of trisomy 13, 18 and 21 foetal tissues at different gestational ages using FISH.
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In man high levels of aneuploidy are seen in spontaneous abortions. Very few autosomal trisomies survive to birth, the three most common being those for chromosome 13, 18 and 21 giving rise to the syndromes named Patau, Edwards and Down respectively. Since the majority of these spontaneously abort, what makes the survivors different from the aborters? Could it be that they have tissue specific mosaicism with the additional normal cell line supporting survival? In this study fluorescence in situ hybridisation was used as a convenient way to detect trisomy in interphase cells. To study the level of mosaicism across gestation, different tissues from 21 trisomic foetuses were analysed using probes for chromosome 13, 18, 21, X and Y. Two trisomy 18 foetuses exhibited mosaicism. Two others, one trisomy 13 and one trisomy 18 had mosaic placentas. There was no clear association between the limited mosaicism seen and severity of the phenotype. We conclude that at least for this sample set, tissue-specific mosaicism was not likely to be responsible for potential survival to birth. (+info)
Sex chromosomal analysis of spermatozoa from infertile men using fluorescence in situ hybridization.
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PURPOSE: To confirm an association between male infertility and chromosome aberrations of spermatozoa, we demonstrated the frequency of numerical abnormalities of spermatozoa from infertile men with abnormal semen parameters compared with fertile controls. METHOD: Sperm cells from 10 infertile patients were investigated for disomy rates of sex chromosomes and chromosome 18 and diploidy by fluorescence in situ hybridization (FISH). All patients showed oligoasthenozoospermia with sperm counts 3-20 x 10(6)/ml and motile rates 0-40%. RESULTS: Regarding XY disomy, a significantly higher frequency was found in 8 of 10 patients as compared to normal fertile men. The disomy rates of chromosome 18, XX, YY, and diploidy rate were not increased. CONCLUSIONS: There is an association between male infertility and embryo with aneuploidy of sex chromosomes. Counseling about possible genetic risks should be provided to the infertile couples planning assisted reproduction treatment. (+info)
Allelic loss at SMAD4 in polyps from juvenile polyposis patients and use of fluorescence in situ hybridization to demonstrate clonal origin of the epithelium.
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Juvenile polyposis syndrome (JPS; Online Mendelian Inheritance in Man2 174900) is a rare Mendelian disorder in which individuals have typical hamartomatous polyps within the gastrointestinal tract. The stromal element of the polyps has classically been thought to be the proliferative component, although epithelial malignancies (largely gastrointestinal cancers) occur more frequently than expected in JPS patients. Germ-line mutations in SMAD4 (DPC4) account for about a third of JPS cases. It has been postulated that the apparent paradox of a stromal lesion predisposing to epithelial malignancy can be resolved by the "landscaper" effect: an abnormal stromal environment affects the development of adjacent epithelial cells, and the resulting regeneration of damaged epithelium leads to an increased risk of cancer. We have found allele loss at the SMAD4 locus on 18q in polyps from JPS individuals with a germ-line SMAD4 mutation, showing that SMAD4 is acting as a tumor suppressor gene in JPS polyps, as it does in sporadic cancers of the gastrointestinal tract. Interphase fluorescence in situ hybridization showed deletion of one copy of SMAD4 in the epithelial component of JPS polyps, but not in the inflammatory infiltrate. Fluorescence in situ hybridization also suggested that a single copy of SMAD4 was present in stromal fibroblasts of JPS polyps. Thus, biallelic inactivation of SMAD4 occurs in both the epithelium and some of the stromal cells in these lesions, suggesting a common clonal origin. Epithelial malignancies almost certainly develop in juvenile polyposis through direct malignant progression of the epithelial component of the hamartomas. SMAD4/DPC4 probably acts as a "gatekeeper" tumor suppressor in juvenile polyps, and there is no need to invoke a "landscaper hypothesis." (+info)
Follicular lymphomas' BCL-2/IgH junctions contain templated nucleotide insertions: novel insights into the mechanism of t(14;18) translocation.
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The human t(14;18) chromosomal translocation is assumed to result from illegitimate rearrangement between BCL-2 and D(H)/J(H) gene segments during V(D)J recombination in early B cells. De novo nucleotides are found inserted in most breakpoints and have been thus far interpreted as nontemplated N region additions. In this report, we have analyzed both direct (BCL-2/J(H)) and reciprocal (D(H)/BCL-2) breakpoints derived from 40 patients with follicular lymphoma with t(14;18). Surprisingly, we found that more than 30% of the breakpoint junctions contain a novel type of templated nucleotide insertions, consisting of short copies of the surrounding BCL-2, D(H), and J(H) sequences. The features of these templated nucleotides, including multiplicity of copies for 1 template and the occurrence of mismatches in the copies, suggest the presence of a short-patch DNA synthesis, templated and error-prone. In addition, our analysis clearly shows that t(14;18) occurs during a very restricted window of B-cell differentiation and involves 2 distinct mechanisms: V(D)J recombination, mediating the breaks on chromosome 14 during an attempted secondary D(H) to J(H) rearrangement, and an additional unidentified mechanism creating the initial breaks on chromosome 18. Altogether, these data suggest that the t(14;18) translocation is a more complex process than previously thought, involving the interaction and/or subversion of V(D)J recombination with multiple enzymatic machineries. (+info)
A novel syndrome of radiation-associated acute myeloid leukemia involving AML1 gene translocations.
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AML1 is a transcriptional activator that is essential for normal hematopoietic development. It is the most frequent target for translocations in acute leukemia. We recently identified 3 patients in whom pancytopenia developed almost 50 years after high-level radiation exposure from nuclear explosions during or after World War II. In all 3 patients, acute myeloid leukemia (AML) eventually developed that had similar characteristics and clinical courses. Cytogenetics from the 3 patients revealed a t(1;21)(p36;q22), a t(18;21)(q21;q22), and a t(19;21)(q13.4;q22). By fluorescent in situ hybridization (FISH), all 3 translocations disrupted the AML1 gene. Two of these AML1 translocations, the t(18;21) and the t(19;21), have not been reported previously. It is possible that the AML1 gene is a target for radiation-induced AML. (Blood. 2000;95:4011-4013) (+info)
No evidence for the involvement of CAG/CTG repeats from within 18q21.33-q23 in bipolar disorder.
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We previously identified 18q21.33-q23 as a candidate region in one BP family and constructed a yeast artificial chromosome (YAC) contig map. Here, we mapped eight known CAG/CTG repeats relative to 18q21.33-q23. We also isolated four CAG/CTG repeats from within the region using CAG/CTG YAC fragmentation, one of which is located in the 5' untranslated region of the CAP2 gene coding for a brain-expressed serine proteinase inhibitor. The triplet repeats located in the 18q21.33-q23 BP candidate region showed no expanded alleles in the linked BP family nor in a BP case-control sample. Moreover, only the CAP2 triplet repeat was polymorphic but no genetic association with BP disorder was observed. (+info)
The genes for major psychosis: aberrant sequence or regulation?
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A number of recent clinical and molecular observations in major psychosis indicate that epigenetic factors may be operational in the origin of major mental illness. This article further develops the idea that epigenetic factors may play an etiopathogenic role in schizophrenia and bipolar affective disorder. The putative role of epigenetic factors is shown by the epigenetic interpretation of genetic association studies of the genes for serotonin 2A (HTR2A) and the dopamine D3 (DRD3) receptors in schizophrenia. The idea of epigenetic polymorphism of genetic alleles is introduced, and it is argued that epigenetic variation may explain a number of controversial and unclear findings in allelic and genotypic association studies of HTR2A and DRD3. In linkage analyses of multiplex families with bipolar affective disorder (BPAD), different loci on chromosome 18 indicated co-segregation of alleles of one parental sex with the disease phenotype, and this finding implies that the epigenetic mechanism of genomic imprinting may be involved. Evidence for genomic imprinting provides the background for epigenetic cloning of BPAD risk factors by searching for differentially modified genes on chromosome 18. Finally, epigenetic studies could be relevant to the better understanding of the molecular action of antipsychotic medications. In addition to this, if epimutations are detected in major psychosis, epigenetic treatment directed at correction of epigenetic status of a specific brain gene may eventually be developed. (+info)