RESUMO
Duplications of 7q11.23, deleted in Williams-Beuren Syndrome, have been implicated in autism spectrum disorders (ASDs). A 1.5 Mb duplication was identified in one girl with severe expressive language deficits and anxiety among 1,142 ASD individuals screened for this duplication. Family-based association studies of Tag-SNPs in three genes (STX1A , CYLN2 and GTF2i) in two multiplex autism family cohorts revealed strong association of two GTF2i SNPs and their haplotype in Cohort 1 and the combined families. The risk alleles and haplotype were associated with severe problems in social interaction and excessive repetitive behaviors. Our findings suggest the GTF2i gene is important in the etiology of autism in individuals with this duplication and in non-duplication cases with severe social interaction problems and repetitive behaviors.
Assuntos
Alelos , Transtornos Globais do Desenvolvimento Infantil/genética , Deleção Cromossômica , Duplicação Cromossômica/genética , Cromossomos Humanos Par 7/genética , Estudos de Associação Genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição TFII/genética , Síndrome de Williams/genética , Regiões 5' não Traduzidas/genética , Transtornos de Ansiedade/genética , Criança , Éxons/genética , Feminino , Triagem de Portadores Genéticos , Marcadores Genéticos/genética , Testes Genéticos , Humanos , Relações Interpessoais , Transtornos do Desenvolvimento da Linguagem/genética , Análise de Sequência com Séries de Oligonucleotídeos , Comportamento EstereotipadoRESUMO
The mouse response to acute Salmonella typhimurium infection is complex, and it is under the influence of several genes, as well as environmental factors. In a previous study, we identified two novel Salmonella susceptibility loci, Ity4 and Ity5, in a (AcB61 x 129S6)F2 cross. The peak logarithm of odds score associated with Ity4 maps to the region of the liver and red blood cell (RBC)-specific pyruvate kinase (Pklr) gene, which was previously shown to be mutated in AcB61. During Plasmodium chabaudi infection, the Pklr mutation protects the mice against this parasite, as indicated by improved survival and lower peak parasitemia. Given that RBC defects have previously been associated with resistance to malaria and susceptibility to Salmonella, we hypothesized that Pklr is the gene underlying Ity4 and that it confers susceptibility to acute S. typhimurium infection in mice. Using a fine mapping approach combined with complementation studies, comparative studies, and functional analysis, we show that Pklr is the gene underlying Ity4 and that it confers susceptibility to acute S. typhimurium infection in mice through its effect on the RBC turnover and iron metabolism.
Assuntos
Predisposição Genética para Doença , Piruvato Quinase/deficiência , Piruvato Quinase/genética , Infecções por Salmonella/genética , Salmonella typhimurium/patogenicidade , Animais , Mapeamento Cromossômico , Cruzamentos Genéticos , Escore Lod , Camundongos , Mutação PuntualRESUMO
Numerous genes have been identified to date that contribute to the host response to systemic Salmonella Typhimurium infection in mice. We have previously identified two loci, Ity2 and Ity3, that control survival to Salmonella infection in the wild-derived inbred MOLF/Ei mouse using a (C57BL/6J x MOLF/Ei)F(2)cross. We validated the existence of these two loci by creating congenic mice carrying each quantitative trait locus (QTL) in isolation. Subcongenic mice generated for each locus allowed us to define the critical intervals underlying Ity2 and Ity3. Furthermore, expression profiling was carried out with the aim of identifying differentially expressed genes within the critical intervals as potential candidate genes. Genomewide expression arrays were used to interrogate expression differences in the Ity2 congenics, leading to the identification of a new candidate gene (Havcr2, hepatitis A virus cellular receptor 2). Interval-specific oligonucleotide arrays were created for Ity3, identifying one potential candidate gene (Chi3l1, chitinase 3-like 1) to be pursued further. The combination of the use of congenics in QTL confirmation and fine mapping and in the identification of candidate genes by expression profiling has been successful and represents a step toward quantitative gene(s) identification.
