RESUMO
A developmental increase in working memory capacity is an important part of cognitive development, and low working memory (WM) capacity is a risk factor for developing psychopathology. Brain activity represents a promising endophenotype for linking genes to behavior and for improving our understanding of the neurobiology of WM development. We investigated gene-brain-behavior relationships by focusing on 18 single-nucleotide polymorphisms (SNPs) located in six dopaminergic candidate genes (COMT, SLC6A3/DAT1, DBH, DRD4, DRD5, MAOA). Visuospatial WM (VSWM) brain activity, measured with functional magnetic resonance imaging, and VSWM capacity were assessed in a longitudinal study of typically developing children and adolescents. Behavioral problems were evaluated using the Child Behavior Checklist (CBCL). One SNP (rs6609257), located ~6.6 kb downstream of the monoamine oxidase A gene (MAOA) on human chromosome X, significantly affected brain activity in a network of frontal, parietal and occipital regions. Increased activity in this network, but not in caudate nucleus or anterior prefrontal regions, was correlated with VSWM capacity, which in turn predicted externalizing (aggressive/oppositional) symptoms, with higher WM capacity associated with fewer externalizing symptoms. There were no direct significant correlations between rs6609257 and behavioral symptoms. These results suggest a mediating role of WM brain activity and capacity in linking the MAOA gene to aggressive behavior during development.
Assuntos
Agressão/fisiologia , Alelos , Encéfalo/fisiopatologia , Transtornos do Comportamento Infantil/genética , Dopamina/fisiologia , Estudos de Associação Genética , Memória de Curto Prazo/fisiologia , Monoaminoxidase/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Fatores Etários , Criança , Transtornos do Comportamento Infantil/fisiopatologia , Bandeamento Cromossômico , Cromossomos Humanos X/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Dopamina beta-Hidroxilase/genética , Endofenótipos , Feminino , Humanos , Controle Interno-Externo , Imageamento por Ressonância Magnética , Masculino , Rede Nervosa/fisiopatologia , Oxigênio/sangue , Receptores de Dopamina D4/genética , Receptores de Dopamina D5/genética , Fatores de Risco , Adulto JovemRESUMO
The human ribosomal protein S19 gene (RPS19) is mutated in approximately 20% of patients with Diamond-Blackfan anemia (DBA), a congenital disease with a specific defect in erythropoiesis. The clinical expression of DBA is highly variable, and subclinical phenotypes may be revealed by elevated erythrocyte deaminase (eADA) activity only. In mice, complete loss of Rps19 results in early embryonic lethality whereas Rps19+/- mice are viable and without major abnormalities including the hematopoietic system. We have performed a detailed analysis of the Rps19+/- mice. We estimated the Rps19 levels in hematopoietic tissues and we analyzed erythrocyte deaminase activity and globin isoforms which are used as markers for DBA. The effect of a disrupted Rps19 allele on a different genetic background was investigated as well as the response to erythropoietin (EPO). From our results, we argue that the loss of one Rps19 allele in mice is fully compensated for at the transcriptional level with preservation of erythropoiesis.
Assuntos
Anemia de Diamond-Blackfan/genética , Eritropoese/genética , Proteínas Ribossômicas/genética , Animais , Biomarcadores/análise , Eritropoetina/farmacologia , Heterozigoto , Camundongos , Camundongos Knockout , Proteínas Ribossômicas/deficiência , Transcrição GênicaRESUMO
Diamond-Blackfan anemia (DBA) is a rare constitutional erythroblastopenia characterized by a specific defect in erythroid differentiation. Recently, mutations in the gene encoding ribosomal protein (RP) S19 were found in a subset of patients with the disease. To characterize further RPS19 mutations and to investigate genotype-phenotype relationships, we screened this gene for mutations in patients with DBA by direct sequencing and Southern-blot analysis. Four novel mutations were identified. A G120A nonsense mutation resulting in a stop at codon 33, a C302T nonsense mutation introducing a premature stop at codon 84, and a 327delG which results in a frame shift at codon 103. A fourth and more complex mutation (TT157-158AA, 160insCT) resulting in a Leu45Gln and a frame shift from codon 47 was found in three affected family members with variable phenotypes. The different clinical expression for identical mutations suggest the presence of other modulating factors for the disease. The mutations presented here further support the role of RPS19 in erythropoietic differentiation and proliferation.
Assuntos
Anemia de Fanconi/genética , Mutação , Proteínas Ribossômicas/genética , Adulto , Sequência de Bases , Pré-Escolar , Códon sem Sentido , DNA/genética , Análise Mutacional de DNA , Primers do DNA/genética , Eritropoese/genética , Feminino , Mutação da Fase de Leitura , Expressão Gênica , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Linhagem , FenótipoRESUMO
Diamond-Blackfan anaemia (DBA) is a constitutional erythroblastopenia characterized by absent or decreased erythroid precursors. The disease, previously mapped to human chromosome 19q13, is frequently associated with a variety of malformations. To identify the gene involved in DBA, we cloned the chromosome 19q13 breakpoint in a patient with a reciprocal X;19 chromosome translocation. The breakpoint occurred in the gene encoding ribosomal protein S19. Furthermore, we identified mutations in RPS19 in 10 of 40 unrelated DBA patients, including nonsense, frameshift, splice site and missense mutations, as well as two intragenic deletions. These mutations are associated with clinical features that suggest a function for RPS19 in erythropoiesis and embryogenesis.
