Mutations in the calcium-related gene IL1RAPL1 are associated with autism

Hum Mol Genet. 2008 Dec 15;17(24):3965-74. doi: 10.1093/hmg/ddn300. Epub 2008 Sep 18.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asperger Syndrome / genetics
  • Asperger Syndrome / pathology
  • Autistic Disorder / genetics*
  • Autistic Disorder / pathology
  • Base Sequence
  • Calcium / physiology*
  • Cell Differentiation / genetics
  • Cell Line
  • Child
  • Codon, Nonsense / genetics
  • Female
  • Frameshift Mutation
  • Genetic Carrier Screening
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Intellectual Disability / genetics
  • Intellectual Disability / pathology
  • Interleukin-1 Receptor Accessory Protein / genetics*
  • Interleukin-1 Receptor Accessory Protein / physiology
  • Male
  • Neurites / metabolism
  • Neurites / pathology
  • Pedigree
  • Rats
  • Sequence Deletion / genetics*


  • Codon, Nonsense
  • IL1RAPL1 protein, human
  • Interleukin-1 Receptor Accessory Protein
  • Calcium