Human Molecular Genetics Advance Access originally published online on September 18, 2008
Human Molecular Genetics 2008 17(24):3965-3974; doi:10.1093/hmg/ddn300
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Mutations in the calcium-related gene IL1RAPL1 are associated with autism
1 Centre for Excellence in Neuromics, CHUM Research Center and Department of Medicine, University of Montreal, Montreal, QC, Canada H2L 4M1 2 CHU Sainte-Justine Research Center, Montreal, QC, Canada H3T 1C5 3 Centre for Research in Neuroscience, McGill University Health Centre, Montreal General Hospital, Montreal, QC, Canada H3G 1A4 4 GeneDx, Gaithersburg, MD, USA 20877 5 Pervasive Developmental Disorders Specialized Clinic, Rivière-des-Prairies Hospital, University of Montreal, Montreal, QC, Canada H1E 1A4 6 Department of Pathology and Cell Biology and Groupe de recherche sur le systeme nerveux central, University of Montreal, Montreal, QC, Canada H3T1J4 7 Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada H4H 1R3 8 Department of Psychiatry, Montreal Children's Hospital, Montreal, QC, Canada H3Z 1P2 9 Department of Statistical Genetics, Research Centre of the Montreal Heart Institute, Montreal, QC, Canada H1T 1C8 10 Department of Physiology, McGill University, McIntyre Medical Sciences Building, Montréal, QC, Canada H3G 1Y6 11 Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4
* To whom correspondence should be addressed at: Centre for Excellence in Neuromics, CHUM Research Center and Department of Medicine, 1560 Sherbrooke E, Room Y-3633, Montreal, Quebec, Canada H2L 4M1. Tel: +1 514890800024699; Fax: +1 5144127602; Email: guy.rouleau{at}umontreal.ca
Received August 6, 2008; Accepted September 12, 2008
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
S2D team is composed of Y. Yang, S. Laurent, A. Noreau, E. Henrion, D. Spiegelman, O. Diallo, L. Destroismaisons, J. Duguay, F. Kuku, L. Karemera, M. Côté, K. Lachapelle, P. Jolivet, A. Raymond, P. Thibodeau, J. Roussel, S. Lamarche, M. Lapointe, M. Liao, K. Daignault and E. Brustein.