title: 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.
authors.affiliation: Centre for Excellence in Neuromics, CHUM Research Center and Department of Medicine, University of Montreal, Montreal, QC, Canada H2L 4M1.
authors.forename: Amélie
authors.initials: A
authors.lastname: Piton
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.forename: Huashan
authors.initials: H
authors.lastname: Peng
authors.forename: Swaroop
authors.initials: S
authors.lastname: Aradhya
authors.forename: Julie
authors.initials: J
authors.lastname: Gauthier
authors.forename: Laurent
authors.initials: L
authors.lastname: Mottron
authors.forename: Nathalie
authors.initials: N
authors.lastname: Champagne
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Lafrenière
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Ridha
authors.initials: R
authors.lastname: Joober
authors.forename: Eric
authors.initials: E
authors.lastname: Fombonne
authors.forename: Claude
authors.initials: C
authors.lastname: Marineau
authors.forename: Patrick
authors.initials: P
authors.lastname: Cossette
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.forename: Pejmun
authors.initials: P
authors.lastname: Haghighi
authors.forename: Pierre
authors.initials: P
authors.lastname: Drapeau
authors.forename: Philip A
authors.initials: PA
authors.lastname: Barker
authors.forename: Salvatore
authors.initials: S
authors.lastname: Carbonetto
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D000818:Animals; D020817:Asperger Syndrome / Q000235:genetics / Q000473:pathology; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002118:Calcium / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002648:Child; D018389:Codon, Nonsense / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D006580:Genetic Carrier Screening; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology; D053577:Interleukin-1 Receptor Accessory Protein / Q000235:genetics* / Q000502:physiology; D008297:Male; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D051381:Rats; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; C407643:IL1RAPL1 protein, human; D053577:Interleukin-1 Receptor Accessory Protein; D002118:Calcium