The Role of Co-Deleted Genes in Neurofibromatosis Type 1 Microdeletions: an Evolutive Approach

Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome that results from dominant loss-of-function mutations mainly in the NF1 gene. Large rearrangements are present in 5–10% of affected patients, generally encompass NF1 neighboring genes, and are correlated with a more severe NF1 phenotype. Evident genotype–phenotype correlations and the importance of the co-deleted genes are difficult to establish. In our study we employed an evolutionary approach to provide further insights into the understanding of the fundamental function of genes that are co-deleted in subjects with NF1 microdeletions. Our goal was to access the ortholog and paralog relationship of these genes in primates and verify if purifying or positive selection are acting on these genes. Fourteen genes were analyzed in twelve mammalian species. Of these, four and ten genes showed positive selection and purifying selection, respectively. The protein, RNF135, showed three sites under positive selection at the RING finger domain, which may have been selected to increase efficiency in ubiquitination routes in primates. The phylogenetic analysis suggests distinct evolutionary constraint between the analyzed genes. With these analyses, we hope to help clarify the correlation of the co-deletion of these genes and the more severe phenotype of NF1

PREVALÊNCIA DA MUTAÇÃO GERMINATIVA TP53 R337H EM PACIENTES ONCOLÓGICOS DIAGNOSTICADOS COM TUMORES COMUMENTE DESCRITOS NA SÍNDROME DE LI-FRAUMENI E SUAS VARIANTES

2

Caracterização de grandes rearranjos em pacientes com neurofibromatose tipo 1 do sul do Brasil

A neurofibromatose tipo 1 é uma desordem hereditária autossômica dominante, de alta penetrância, causada por diversas alterações moleculares que acarretam em perda de função do gene NF1. A proteína codificada por esse gene possui um domínio de GTPase que regula negativamente a atividade da proteína RAS, sendo que a perda funcional de NF1 resulta no aumento da proliferação celular e no consequente aumento da chance de desenvolvimento de tumores. Os grandes rearranjos de NF1, dos mais diferentes tipos, estão presentes em 5-10% dos pacientes e normalmente estão relacionados com um quadro clínico mais grave. Neste estudo, além da descrição de casos de pacientes portadores de grandes rearranjos diagnosticados no Hospital de Clínicas de Porto Alegre, também foi estudada a possibilidade de implementação de outros genes relacionados com o fenótipo da doença no diagnóstico molecular de NF1. Para isso, foram pesquisadas evidências que indiquem a importância dos genes deletados nos grandes rearranjos, através de revisão bibliográfica e de análises in silico, que também facilitam a escolha de genes alvo para estudos posteriores. Foi demonstrado que além de NF1, seria interessante avaliar as alterações adicionais nos genes RNF135 e SUZ12 nas análises moleculares dos casos clínicos de neurofibromatose tipo 1, visto que alterações nesses genes parecem modificar o fenótipo da doença. Os genes RNF135, SUZ12, OMG, ADAP2, ADAP1, RAB11FIP4 e RAB11FIP3, a maioria adjacente ao gene NF1, são fortes candidatos a serem modificadores de fenótipo e podem fazer parte de estudos posteriores.Neurofibromatosis type 1 is an autosomal dominant inherited disorder, with high penetrance, caused by different molecular changes that lead to loss of function of the NF1 gene. The protein encoded by this gene has a GTPase domain that negatively regulates RAS protein activity, and the functional loss of NF1 results in an increased cell proliferation and consequently in an increased chance of tumor development. The different types of NF1 large rearrangements are present in 5-10% of patients and are usually related to a more severe clinical condition. In this study, NF1 patients diagnosed at Hospital de Clínicas de Porto Alegre were screened for large rearrangements and clinically characterized; the possibility of the incorporation of other genes related to disease phenotype in NF1 molecular diagnosis was also studied. For this purpose, was researched evidence indicating the importance of the deleted genes in large rearrangements have been searched through literature review and in silico analysis, in order to facilitate the choice of target genes for further study. It was demonstrated that besides NF1 gene, it would be interesting to evaluate additional changes in SUZ12 and RNF135 genes in the molecular analysis of clinical cases of neurofibromatosis type 1, since changes in these genes seem to modify the disease phenotype. The RNF135, SUZ12, ADAP2, OMG, ADAP1, RAB11FIP4 and RAB11FIP3 genes, most of them localized adjacent to the NF1 gene, are strong candidates to be phenotype modifiers and can take part in subsequent studies

PREVALÊNCIA DA MUTAÇÃO GERMINATIVA TP53 R337H EM PACIENTES ONCOLÓGICOS DIAGNOSTICADOS COM TUMORES COMUMENTE DESCRITOS NA SÍNDROME DE LI-FRAUMENI E SUAS VARIANTES

2

Caracterização de grandes rearranjos em pacientes com neurofibromatose tipo 1 do sul do Brasil

A neurofibromatose tipo 1 é uma desordem hereditária autossômica dominante, de alta penetrância, causada por diversas alterações moleculares que acarretam em perda de função do gene NF1. A proteína codificada por esse gene possui um domínio de GTPase que regula negativamente a atividade da proteína RAS, sendo que a perda funcional de NF1 resulta no aumento da proliferação celular e no consequente aumento da chance de desenvolvimento de tumores. Os grandes rearranjos de NF1, dos mais diferentes tipos, estão presentes em 5-10% dos pacientes e normalmente estão relacionados com um quadro clínico mais grave. Neste estudo, além da descrição de casos de pacientes portadores de grandes rearranjos diagnosticados no Hospital de Clínicas de Porto Alegre, também foi estudada a possibilidade de implementação de outros genes relacionados com o fenótipo da doença no diagnóstico molecular de NF1. Para isso, foram pesquisadas evidências que indiquem a importância dos genes deletados nos grandes rearranjos, através de revisão bibliográfica e de análises in silico, que também facilitam a escolha de genes alvo para estudos posteriores. Foi demonstrado que além de NF1, seria interessante avaliar as alterações adicionais nos genes RNF135 e SUZ12 nas análises moleculares dos casos clínicos de neurofibromatose tipo 1, visto que alterações nesses genes parecem modificar o fenótipo da doença. Os genes RNF135, SUZ12, OMG, ADAP2, ADAP1, RAB11FIP4 e RAB11FIP3, a maioria adjacente ao gene NF1, são fortes candidatos a serem modificadores de fenótipo e podem fazer parte de estudos posteriores.Neurofibromatosis type 1 is an autosomal dominant inherited disorder, with high penetrance, caused by different molecular changes that lead to loss of function of the NF1 gene. The protein encoded by this gene has a GTPase domain that negatively regulates RAS protein activity, and the functional loss of NF1 results in an increased cell proliferation and consequently in an increased chance of tumor development. The different types of NF1 large rearrangements are present in 5-10% of patients and are usually related to a more severe clinical condition. In this study, NF1 patients diagnosed at Hospital de Clínicas de Porto Alegre were screened for large rearrangements and clinically characterized; the possibility of the incorporation of other genes related to disease phenotype in NF1 molecular diagnosis was also studied. For this purpose, was researched evidence indicating the importance of the deleted genes in large rearrangements have been searched through literature review and in silico analysis, in order to facilitate the choice of target genes for further study. It was demonstrated that besides NF1 gene, it would be interesting to evaluate additional changes in SUZ12 and RNF135 genes in the molecular analysis of clinical cases of neurofibromatosis type 1, since changes in these genes seem to modify the disease phenotype. The RNF135, SUZ12, ADAP2, OMG, ADAP1, RAB11FIP4 and RAB11FIP3 genes, most of them localized adjacent to the NF1 gene, are strong candidates to be phenotype modifiers and can take part in subsequent studies