Thesis (Ph. D.)--Katholieke Universiteit Nijmegen, 1966.

Thesis (Ph. D.)--Katholieke Universiteit Nijmegen, 1966.

DiGeorge syndrome (DGS) is a developmental defect associated with deletions in chromosomal region 22q11.2. Recently, other syndromes (Velo-Cardio-Facial syndrome, Conotruncal Anomaly Face syndrome, isolated conotruncal cardiopathy) with overlapping phenotypes have been found to be associated with deletions of a similar extent in this chromosomal region. All these syndromes have been grouped under the acronym CATCH 22 (Cardiac defect, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia, chromosome 22q11.2 deletions). In order to characterize genetically this group of syndromes, we have searched for deletions in the 22q11.2 chromosomal region by fluorescence in situ hybridization (FISH). A set of 6 cosmid probes dispersed within the whole length of the DGS deleted region was used to screen 23 patients. A 22q11.2 deletion was observed in 96% of the patients studied. Furthermore, there does not seem to exist any correlation between the size of the deletion and the phenotype observed, since the majority of patients studied, although widely divergent in their clinical manifestation of DGS, appeared to present the same extent of deletion in this genomic region. / There appears to be a predominance of deletion-bearing mothers in familial CATCH 22 when published pedigrees are examined. Furthermore, our own familial cases and the sporadic cases where the parental origin of the deletion could be deduced using a chromosome 22 short arm heteromorphisms seem to confirm this tendency. Because we had isolated a CA-repeat locus mapping within the DGS deleted region, the parental origin of the deletion in sporadic DGS/VCFS cases was studied by assessing the inheritance pattern of this microsatellite marker. The deleted portion of chromosome 22 was of maternal origin in 16 out of 22 cases (72%). When cases of sporadic, familial and unbalanced translocation inheritance reported in the literature were pooled with these results, there appears to be a net tendency for the deletions to be of maternal origin in CATCH 22 (70 deletions of maternal origin, 21 of paternal origin, X$ sp2$ = 26.4, p $<$ 0.0001). / In order to identify the molecular defect underlying DGS, we embarked on a positional cloning approach. A detailed physical map of the 22q11.2 region was made using one- and two-color FISH on metaphases and G$ sb0$ interphase nuclei, and by hybridization to a chromosome 22 hybrid panel. This permitted delineation of a critical region, within which the breakpoint of a balanced translocation carrier affected with DGS was mapping. This breakpoint was cloned by the construction of cosmid contigs, and a novel gene mapped to this region was isolated. The gene potentially encodes an adhesion receptor, and is not interrupted by the balanced translocation breakpoint. Possible mechanisms through which this gene can be involved in the pathogenesis of DGS are presented. / This research project has contributed toward the understanding of the genetics of DGS and related syndromes. Furthermore, a candidate gene for the CATCH 22 syndromes has been isolated and further work will confirm whether it plays a major role in the pathogenesis of these syndromes.

No description available.

Thesis (Ph. D.)--University of Chicago, Dept. of Pathaology, 2002. / Includes bibliographical references. Also available on the Internet.

Thesis--Universidade Estadual de Campinas, 1979.

Thesis--Universidade Estadual de Campinas, 1979.

This investigation reorganizes and identifies chromosomal anomalies and delineates the associated clinical findings. The present investigation involved 37 individuals with anomalies of chromosome 22. The clinical profile with the corresponding cytogenetic anomalies was studied.

Orientador: Agnes Cristina Fett Conte / Banca: Cláudia Regina Bonini Domingos / Banca: Flávio Naoum / Resumo: As Síndromes Mielodisplásicas (SMD) definem um grupo de doenças clonais das células hematopoéticas caracterizadas por citopenias, displasia em uma ou mais linhagens celulares mielóides, hematopoese ineficaz e aumento do risco de evolução para leucemia mielóide aguda. A frequência de doentes que progridem para o câncer varia com o subtipo de SMD, de acordo com a classificação da Organização Mundial da Saúde. As SMD são consideradas doenças pré-malignas e, ao contrário de outras doenças hematológicas, como as leucemias, estão geralmente associadas a anomalias cromossômicas desequilibradas. Estas consistem principalmente em deleções, translocações e alterações numéricas. Também são frequentemente observadas perdas de material genético, com consequente inativação de genes supressores tumorais. Estes genes controlam mecanismos biológicos vitais, como reparo do DNA, crescimento e morte celular programada. Um exemplo é o supressor de tumor RASSF1A (Ras-association domain family 1, isoform A), mapeado em 3p21.3. A falta de expressão deste gene e taxas elevadas de mutações, especialmente envolvendo os exons 3, 4 e 5, foram descritas em diversos tipos de cancêr, mas nunca foram investigadas em SMD. Neste contexto, este projeto teve como proposta investigar a presença de alterações cromossômicas e de mutações nos exons 3, 4 e 5 do gene RASSF1A em indivíduos com SMD ao diagnóstico e em controles normais. Foram estudados 50 casos dos quais foram realizadas culturas de curta duração (24 horas) de células de medula óssea sem estimulação mitogênica e sequenciamento direto dos exons de interesse. Quatro casos (8%) apresentaram alterações cromossômicas, caracterizadas como hipodiploidia em dois casos, monossomia do cromossomo 7 em um e um cariótipo complexo envolvendo os cromossomos 3, 5 e 11 em outro. A análise molecular dos exons 3, 4 e 5 dos 50 casos revelou dois (4%) casos com o polimorfismo ... / Abstract: The myelodysplastic syndromes (MDS) are characterized by cytopenias, dysplasia in one or more myeloid cell lines, ineffective hematopoiesis and an increased risk of acute myeloid leukemia (AML) transformation. The rate of patients who progress to AML varies by subtype of disease, according to the World Health Organization classification. The MDS are considered premalignant diseases and unlike of other hematological diseases, such as leukemia, are mostly associated with unbalanced chromosomal abnormalities, as deletions, translocations and numerical changes, beyond loss of genetic material with consequent tumor suppressor genes inactivation, which can control biological mechanisms such as DNA repair, growth and programmed cell death. An example is the tumor suppressor RASSF1A (Ras-association domain family 1, isoform A) mapped in 3p21.3. The high mutation rates and no expression of this gene, mainly exons 3, 4 and 5, have been described in several types of cancer but have never been investigated in MDS. Thereby chromosomal changes and mutations in exons 3, 4 and 5 from RASSF1A of the bone marrow cells from 50 cases the diagnosis of MDS were investigated. The assays were accomplished for 24 hours applying bone marrow cells without mitogenic stimulation and the exons were straight sequenced, where four samples (8%) had chromosomal abnormalities, characterized for hypodyploidy (two cases), monosomy 7 and complex karyotype involving chromosomes 3, 5 and 11. Molecular analysis revealed two (4%) other cases with Ala133Ser polymorphism (A133S) in exon 3. The cytogenetic changes observed are related to the MDS developed, while the polymorphism has been proposed to be involved in some types of cancers predisposition. The results can support other studies which are searching for genetic factors involved in the pathogenesis of MDS / Mestre

Made available in DSpace on 2015-04-09T12:28:26Z (GMT). No. of bitstreams: 0 Previous issue date: 2014-02-21Bitstream added on 2015-04-09T12:47:34Z : No. of bitstreams: 1 000811842.pdf: 747851 bytes, checksum: 12d5b852f7d8f1956044b6f1de50c444 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / As Síndromes Mielodisplásicas (SMD) definem um grupo de doenças clonais das células hematopoéticas caracterizadas por citopenias, displasia em uma ou mais linhagens celulares mielóides, hematopoese ineficaz e aumento do risco de evolução para leucemia mielóide aguda. A frequência de doentes que progridem para o câncer varia com o subtipo de SMD, de acordo com a classificação da Organização Mundial da Saúde. As SMD são consideradas doenças pré-malignas e, ao contrário de outras doenças hematológicas, como as leucemias, estão geralmente associadas a anomalias cromossômicas desequilibradas. Estas consistem principalmente em deleções, translocações e alterações numéricas. Também são frequentemente observadas perdas de material genético, com consequente inativação de genes supressores tumorais. Estes genes controlam mecanismos biológicos vitais, como reparo do DNA, crescimento e morte celular programada. Um exemplo é o supressor de tumor RASSF1A (Ras-association domain family 1, isoform A), mapeado em 3p21.3. A falta de expressão deste gene e taxas elevadas de mutações, especialmente envolvendo os exons 3, 4 e 5, foram descritas em diversos tipos de cancêr, mas nunca foram investigadas em SMD. Neste contexto, este projeto teve como proposta investigar a presença de alterações cromossômicas e de mutações nos exons 3, 4 e 5 do gene RASSF1A em indivíduos com SMD ao diagnóstico e em controles normais. Foram estudados 50 casos dos quais foram realizadas culturas de curta duração (24 horas) de células de medula óssea sem estimulação mitogênica e sequenciamento direto dos exons de interesse. Quatro casos (8%) apresentaram alterações cromossômicas, caracterizadas como hipodiploidia em dois casos, monossomia do cromossomo 7 em um e um cariótipo complexo envolvendo os cromossomos 3, 5 e 11 em outro. A análise molecular dos exons 3, 4 e 5 dos 50 casos revelou dois (4%) casos com o polimorfismo ... / The myelodysplastic syndromes (MDS) are characterized by cytopenias, dysplasia in one or more myeloid cell lines, ineffective hematopoiesis and an increased risk of acute myeloid leukemia (AML) transformation. The rate of patients who progress to AML varies by subtype of disease, according to the World Health Organization classification. The MDS are considered premalignant diseases and unlike of other hematological diseases, such as leukemia, are mostly associated with unbalanced chromosomal abnormalities, as deletions, translocations and numerical changes, beyond loss of genetic material with consequent tumor suppressor genes inactivation, which can control biological mechanisms such as DNA repair, growth and programmed cell death. An example is the tumor suppressor RASSF1A (Ras-association domain family 1, isoform A) mapped in 3p21.3. The high mutation rates and no expression of this gene, mainly exons 3, 4 and 5, have been described in several types of cancer but have never been investigated in MDS. Thereby chromosomal changes and mutations in exons 3, 4 and 5 from RASSF1A of the bone marrow cells from 50 cases the diagnosis of MDS were investigated. The assays were accomplished for 24 hours applying bone marrow cells without mitogenic stimulation and the exons were straight sequenced, where four samples (8%) had chromosomal abnormalities, characterized for hypodyploidy (two cases), monosomy 7 and complex karyotype involving chromosomes 3, 5 and 11. Molecular analysis revealed two (4%) other cases with Ala133Ser polymorphism (A133S) in exon 3. The cytogenetic changes observed are related to the MDS developed, while the polymorphism has been proposed to be involved in some types of cancers predisposition. The results can support other studies which are searching for genetic factors involved in the pathogenesis of MDS