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Common Genetic Abnormality (common + genetic_abnormality)

Distribution by Scientific Domains

Medical Sciences	75%

Selected Abstracts

Evidence for the multigenic inheritance of schizophrenia

AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 8 2001
Robert Freedman
Abstract Schizophrenia is assumed to have complex inheritance because of its high prevalence and sporadic familial transmission. Findings of linkage on different chromosomes in various studies corroborate this assumption. It is not known whether these findings represent heterogeneous inheritance, in which various ethnic groups inherit illness through different major gene effects, or multigenic inheritance, in which affected individuals inherit several common genetic abnormalities. This study therefore examined inheritance of schizophrenia at different genetic loci in a nationally collected European American and African American sample. Seventy-seven families were previously genotyped at 458 markers for the NIMH Schizophrenia Genetics Initiative. Initial genetic analysis tested a dominant model, with schizophrenia and schizoaffective disorder, depressed type, as the affected phenotype. The families showed one genome-wide significant linkage (Z,=,3.97) at chromosome 15q14, which maps within 1 cM of a previous linkage at the ,7-nicotinic receptor gene. Chromosome 10p13 showed suggestive linkage (Z,=,2.40). Six others (6q21, 9q32, 13q32, 15q24, 17p12, 20q13) were positive, with few differences between the two ethnic groups. The probability of each family transmitting schizophrenia through two genes is greater than expected from the combination of the independent segregation of each gene. Two trait-locus linkage analysis supports a model in which genetic alleles associated with schizophrenia are relatively common in the general population and affected individuals inherit risk for illness through at least two different loci. © 2001 Wiley-Liss, Inc. [source]

EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma

GENES, CHROMOSOMES AND CANCER, Issue 12 2007
Cristina R. Antonescu
The molecular hallmark of angiomatoid fibrous histiocytoma (AFH) is not well defined, with only six cases with specific gene fusions reported to date, consisting of either FUS-ATF1 or EWSR1-ATF1. To address this, we investigated the presence of FUS-ATF1, EWSR1-ATF1, and the highly related EWSR1-CREB1 fusion in a group of nine AFHs. All cases were subjected to RT-PCR for EWSR1-ATF1 and EWSR1-CREB1. FISH for EWSR1 and FUS rearrangements was performed in most cases. Transcriptional profiling was performed in three tumors and their gene expression was compared to five clear cell sarcomas expressing either the EWSR1-ATF1 or EWSR1-CREB1 fusion. By RT-PCR, eight out of nine tumors showed the presence of the EWSR1-CREB1 fusion, while one had an EWSR1-ATF1 transcript. FISH showed evidence of EWSR1 rearrangement in seven out of eight cases. Karyotypic analysis performed in one tumor showed a t(2;22)(q33;q12). High transcript levels were noted for TFE3 in AFH tumors, while overexpression of genes involved in melanogenesis, such as MITF, GP100, and MET was noted in somatic clear cell sarcomas. We report for the first time the presence of EWSR1-CREB1 in AFH, which now appears to be the most frequent gene fusion in this tumor. EWSR1-CREB1 is a novel translocation recently described in clear cell sarcoma of the GI tract. EWSR1-ATF1, identified in some AFH cases, is the most common genetic abnormality in soft tissue clear cell sarcoma. Thus, identical fusions involving ATF1 and CREB1 are found in two distinct sarcomas, which may be able to transform two different types of mesenchymal precursor cells, unlike most other sarcoma gene fusions. © 2007 Wiley-Liss, Inc. [source]

Mutations of the PTPN11 gene in therapy-related MDS and AML with rare balanced chromosome translocations

GENES, CHROMOSOMES AND CANCER, Issue 6 2007
Debes H. Christiansen
Activating mutations of the PTPN11 gene encoding the SHP2 tyrosine phosphatase is the most common genetic abnormality in juvenile myelomonocytic leukemia and is sporadically observed in myelodysplasia (MDS) and acute myeloid leukemia (AML). An unselected series of 140 patients with therapy-related MDS or AML were investigated for mutations of PTPN11 in Exons 3, 4, 8, and 13. Four cases had mutations of the gene; three of these had deletions or loss of chromosome arm 7q. Two cases had rare balanced translocations to chromosome band 21q22 with rearrangement of the RUNX1 gene and the other two patients had rare balanced translocations to chromosome band 3q26 with rearrangement of the EVI1 gene. The findings support cooperation between so called Class I and Class II mutations in leukemogenesis. © 2007 Wiley-Liss, Inc. [source]

Discriminating functional and non-functional p53 in human tumours by p53 and MDM2 immunohistochemistry

THE JOURNAL OF PATHOLOGY, Issue 3 2005
R Nenutil
Abstract Mutation and/or loss of the TP53 tumour suppressor gene is the single most common genetic abnormality in human cancer. The majority of TP53 mutations lead to stabilization of the protein, so that immunohistochemical staining for p53 can suggest mutation status in many cases. However, various false-positive and false-negative situations mean that simple immunostaining for p53 is not informative in a substantial number of tumours. In the present study, a series of 119 human cancers were immunostained using a highly sensitive technique that detects the low levels of wild-type protein expressed in normal cells, such that homozygous gene deletion or non-sense TP53 mutation can be identified by an absence of staining. TP53 gene status was also assessed using FASAY as a genetic/functional screen and in selected cases by direct sequencing. A quantitative scoring system was employed to assess p53 levels, and p53 post-translational modification was evaluated using antibodies that detect specific phosphorylation sites. Phosphorylated p53 correlated with total p53 levels and did not improve the prediction of TP53 mutation status. The transcriptional activity of TP53 was determined by staining for two downstream target genes, p21WAF1 and MDM2, and statistical correlations between MDM2/p21WAF1 and p53 were found in tumours with wild-type, but not mutant TP53. Measurement of staining for p53 and MDM2 accurately identifies the TP53 status of tumours. This simple and cost-effective method, applicable to automated staining and quantitation methods, improves the identification of TP53 status over standard methods for p53 immunostaining and provides information about tumour p53 phenotype that is complementary to genotyping data. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source]