Mutations in the calcium-related gene IL1RAPL1 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, Guy A. Rouleau

Research output: Contribution to journalArticlepeer-review

164 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3965-3974
Number of pages10
JournalHuman molecular genetics
Issue number24
StatePublished - 2008
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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