RESUMO
BACKGROUND: Autism spectrum disorders (ASD) are highly inherited developmental syndromes, resulting from a complex interaction between environmental and genetic factors. To date, only a limited number of genetic variants have been discovered with respect to autism, and their contribution to the development of the disorder has not been clearly determined. Investigation of specific autistic symptomatology may improve the chances of identifying related genes and may help to better understand these disorders. MATERIALS AND METHODS: We investigated the contribution of 80 genetic variants in 15 serotonin genes to ASD phenotypes [intelligence quotation (IQ), intellectual disability (ID) and language onset delay (LD)] in a cohort of 141 children and young adults (121 male patients and 20 female patients, average age 14.5±5.1 years). RESULTS: Two polymorphisms in the HTR2B gene, rs10194776 and rs16827801, were associated with IQ (P=0.0004 and 0.003, respectively), ID (P=0.02 and 0.03) and LD (P=0.04 and 0.004). Nominal associations were also detected between the ASD phenotypes investigated and 5-HT2A, 5-HT4 and 5-HT6 genetic variants. CONCLUSION: Our study provides evidence of the contribution of serotonergic variants to IQ, ID and LD in ASD patients.
Assuntos
Transtorno Autístico/genética , Polimorfismo Genético , Serotonina/genética , Adolescente , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Estatística como Assunto , Adulto JovemRESUMO
Neurexins are synaptic plasma membrane proteins encoded by three genes (NRXN1, -2, -3) with alternative promoters. Mutations in neurexin genes have been identified in different neurodevelopmental disorders, including autism. Recently, two point mutations altering the translation initiation site of NRXN1ß (c.-3G>T and c.3G>T) have been described in patients with autism and mental retardation. In this study, we analyzed the NRXN1ß gene in a sample of 153 patients with autism. We report the identification of a novel mutation, c.3G>A (p.Met1), affecting the translation initiation site. Expression analysis showed that the c.3G>A mutation switches the translation start site of NRXN1ß to an in-frame downstream methionine and decreases synaptic levels of the mutant protein in cultured neurons. These data reinforce a role for synaptic defects of NRXN1ß in neurodevelopmental disorders.
Assuntos
Transtorno Autístico/genética , Códon de Iniciação/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Sinapses/metabolismo , Adolescente , Animais , Sequência de Bases , Feminino , Células HEK293 , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , RatosRESUMO
Impairment of language abilities is a common feature in autistic individuals. Heterozygous mutations in the Forkhead Box P2 (FOXP2) gene lead to a severe spoken language disorder. Recently, several studies have pinpointed the involvement of common variants of the Contactin-Associated Protein-Like 2 (CNTNAP2) gene, whose transcription is regulated by the product of FOXP2, in several disorders characterized by language impairments such as autism, specific language impairment (SLI), and selective mutism (SM). In the present study, common variants of the FOXP2 and the CNTNAP2 genes were analyzed through a case-control association study in 322 Spanish autistic patients and 524 controls. The results of this study suggest that common variants of FOXP2 are unlikely to contribute to autism susceptibility, in agreement with previous findings. Furthermore, we failed to replicate in our sample a previous association finding of two single nucleotide polymorphisms (rs2710102 and rs7794745) in the CNTNAP2 gene with autism. No evidence for the association of these genes with language traits was observed in our analysis.
Assuntos
Transtorno Autístico/genética , Fatores de Transcrição Forkhead/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Idioma , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Adolescente , Estudos de Casos e Controles , Feminino , Marcadores Genéticos , Humanos , Masculino , EspanhaRESUMO
OBJECTIVES: Neurotransmitter systems and neurotrophic factors can be considered strong candidates for autism spectrum disorder (ASD). The serotoninergic and dopaminergic systems are involved in neurotransmission, brain maturation and cortical organization, while neurotrophic factors (NTFs) participate in neurodevelopment, neuronal survival and synapses formation. We aimed to test the contribution of these candidate pathways to autism through a case-control association study of genes selected both for their role in central nervous system functions and for pathophysiological evidences. METHODS: The study sample consisted of 326 unrelated autistic patients and 350 gender-matched controls from Spain. We genotyped 369 tagSNPs to perform a case-control association study of 37 candidate genes. RESULTS: A significant association was obtained between the DDC gene and autism in the single-marker analysis (rs6592961, P = 0.00047). Haplotype-based analysis pinpointed a four-marker combination in this gene associated with the disorder (rs2329340C-rs2044859T-rs6592961A-rs11761683T, P = 4.988e-05). No significant results were obtained for the remaining genes after applying multiple testing corrections. However, the rs167771 marker in DRD3, associated with ASD in a previous study, displayed a nominal association in our analysis (P = 0.023). CONCLUSIONS: Our data suggest that common allelic variants in the DDC gene may be involved in autism susceptibility.