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

Abstract

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.

Interleukin-1 Receptor Accessory Protein Organizes Neuronal Synaptogenesis as a Cell Adhesion Molecule

“…We recently showed that IL1RAPL1 organizes synapse formation of mouse cortical neurons through transsynaptic interaction with PTP␦ . Since IL1RAPL1 is responsible for nonsyndromic MR and is associated with autism (Carrié et al, 1999;Piton et al, 2008), we propose that the impairment of synapse formation may underlie the pathogenesis of certain forms of MR and autism. In addition, IL1RAPL2, a close relative of IL1RAPL1 sharing 61.5% amino acid sequence identity, showed a weak synaptogenic activity in fibroblast-neuron mixed culture assay (data not shown).…”

Direct single-molecule observation of calcium-dependent misfolding in human neuronal calcium sensor-1

“…NCS-1 has also been linked to serious neurodegenerative disorders including schizophrenia, bipolar disorder (BD) (32), and autism (33,34). However, the dysfunctions of NCS-1 are poorly characterized on the molecular level, and whether they involve altered functional profiles or loss of function due to formation of misfolded states is currently unknown.…”

The guanine-exchange factor Ric8a binds the calcium sensor NCS-1 to regulate synapse number and probability of release

“…Human interleukin-1 receptor accessory protein-like (IL1RAPL1) interacts with NCS-1, and both proteins are involved in X-linked mental retardation and autism (Bahi et al, 2003;Pavlowsky et al, 2010). Furthermore, a missense (R102Q) mutation in NCS-1 has been reported in one case of autism (Piton et al, 2008), and schizophrenic and bipolar disorder patients show an excess of NCS-1 in their dorsolateral prefrontal cortex (Koh et al, 2003) and a decrease of the protein in leukocytes (Torres et al, 2009). In view of the large repertoire of functional interactions reported so far, the search for unifying mechanisms that could account for the biology of this Ca 2+ sensor is justified.…”