Human Molecular Genetics Advance Access published online on September 18, 2008
Human Molecular Genetics, 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, H2L 4M1, Canada 2 CHU Sainte-Justine Research Center, Montreal, QC, H3T 1C5, Canada 3 Centre for Research in Neuroscience, McGill University Health Centre, Montreal General Hospital, Montreal, QC, H3G 1A4, Canada 4 GeneDx, Gaithersburg, MD, 20877, USA 5 Pervasive Developmental Disorders Specialized Clinic, Rivière-des-Prairies Hospital, University of Montreal, Montreal, QC, H1E 1A4, Canada 6 Department of Pathology and Cell Biology and Groupe de recherche sur le systeme nerveux central, University of Montreal, Montreal, QC, H3T1J4, Canada 7 Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, QC, H4H 1R3, Canada 8 Department of Psychiatry, Montreal Children's Hospital, Montreal, QC, H3Z 1P2, Canada 9 Research Centre of the Montreal Heart Institute, Department of Statistical Genetics, Montreal, QC, H1T 1C8, Canada 10 Department of Physiology, McGill University, McIntyre Medical Sciences Building, Montréal, QC, H3G 1Y6, Canada 11 Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada
* Address for correspondence and reprints: Dr. Guy A. Rouleau, Centre for Excellence in Neuromics, CHUM Research Center and Department of Medicine, 1560 Sherbrooke E, Room Y-3633, Montreal, Quebec, Canada H2L 4M1. E-mail: guy.rouleau{at}umontreal.ca. Phone: 1-514-890-8000-24699/Fax: 1-514-412-7602
Received August 6, 2008; Revised September 12, 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 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 nonsynonymous 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 to 7 of IL1RAPL1 in three brothers with autism and/or mental retardation. 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 mental retardation to high functioning autism.
# The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Authors.
& S2D team is composed of Yang Y., Laurent S., Noreau A.., Henrion E., Spiegelman D., Diallo O., Destroismaisons L., Duguay J., Kuku F., Karemera L., Côté M., Lachapelle K., Jolivet P., Raymond A., Thibodeau P., Roussel J., Lamarche S., Lapointe M., Liao M., Daignault K. and E. Brustein.