Mutations in the calcium-related gene IL1RAPL1 are associated with autism
| Autor: | Marie-Pierre Dubé, Jacques L. Michaud, S D team, Patrick Cossette, Pierre Drapeau, Amélie Piton, Claude Marineau, Swaroop Aradhya, Ronald G. Lafrenière, Philip A. Barker, Huashan Peng, Nathalie Champagne, Fadi F. Hamdan, Laurent Mottron, Ridha Joober, Guy A. Rouleau, Julie Gauthier, Eric Fombonne, Pejmun Haghighi, Salvatore Carbonetto |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Biology medicine.disease_cause Hippocampus Frameshift mutation Cell Line Exon Intellectual Disability Genetics medicine Neurites Missense mutation Coding region Animals Humans Asperger Syndrome Autistic Disorder Child Frameshift Mutation Molecular Biology Genetics (clinical) X chromosome Sequence Deletion Mutation Base Sequence Genetic Carrier Screening Cell Differentiation General Medicine medicine.disease Pedigree Rats High-functioning autism Codon Nonsense Autism Calcium Female Interleukin-1 Receptor Accessory Protein |
| Zdroj: | Human molecular genetics. 17(24) |
| ISSN: | 1460-2083 |
| Popis: | In a systematic sequencing screen of synaptic genes on the X chromosome, we have identified an autistic female without mental retardation (MR) who carries a de novo frameshift Ile367SerfsX6 mutation in Interleukin-1 Receptor Accessory Protein-Like 1 (IL1RAPL1), a gene implicated in calcium-regulated vesicle release and dendrite differentiation. We showed that the function of the resulting truncated IL1RAPL1 protein is severely altered in hippocampal neurons, by measuring its effect on neurite outgrowth activity. We also sequenced the coding region of the close related member IL1RAPL2 and of NCS-1/FREQ, which physically interacts with IL1RAPL1, in a cohort of subjects with autism. The screening failed to identify non-synonymous variant in IL1RAPL2, whereas a rare missense (R102Q) in NCS-1/FREQ was identified in one autistic patient. Furthermore, we identified by comparative genomic hybridization a large intragenic deletion of exons 3-7 of IL1RAPL1 in three brothers with autism and/or MR. This deletion causes a frameshift and the introduction of a premature stop codon, Ala28GlufsX15, at the very beginning of the protein. All together, our results indicate that mutations in IL1RAPL1 cause a spectrum of neurological impairments ranging from MR to high functioning autism. |
| Databáze: | OpenAIRE |
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