Journal Article

Mutations in the calcium-related gene <i>IL1RAPL1</i> are associated with autism

Amélie Piton, Jacques L. Michaud, Huashan Peng, Swaroop Aradhya, Julie Gauthier, Laurent Mottron, Nathalie Champagne, Ronald G. Lafrenière, Fadi F. Hamdan, Ridha Joober, Eric Fombonne, Claude Marineau, Patrick Cossette, Marie-Pierre Dubé, Pejmun Haghighi, Pierre Drapeau, Philip A. Barker, Salvatore Carbonetto and Guy A. Rouleau

in Human Molecular Genetics

Volume 17, issue 24, pages 3965-3974
Published in print December 2008 | ISSN: 0964-6906
Published online September 2008 | e-ISSN: 1460-2083 | DOI:
Mutations in the calcium-related gene IL1RAPL1 are associated with autism

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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.

Journal Article.  5519 words.  Illustrated.

Subjects: Genetics and Genomics

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