Human Molecular Genetics 2015-02-15

Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis.

Mariana Ramos-Brossier, Caterina Montani, Nicolas Lebrun, Laura Gritti, Christelle Martin, Christine Seminatore-Nole, Aurelie Toussaint, Sarah Moreno, Karine Poirier, Olivier Dorseuil, Jamel Chelly, Anna Hackett, Jozef Gecz, Eric Bieth, Anne Faudet, Delphine Heron, R Frank Kooy, Bart Loeys, Yann Humeau, Carlo Sala, Pierre Billuart

文献索引：Hum. Mol. Genet. 24(4) , 1106-18, (2015)

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摘要

Mutations in interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene have been associated with non-syndromic intellectual disability (ID) and autism spectrum disorder. This protein interacts with synaptic partners like PSD-95 and PTPδ, regulating the formation and function of excitatory synapses. The aim of this work was to characterize the synaptic consequences of three IL1RAPL1 mutations, two novel causing the deletion of exon 6 (Δex6) and one point mutation (C31R), identified in patients with ID. Using immunofluorescence and electrophysiological recordings, we examined the effects of IL1RAPL1 mutant over-expression on synapse formation and function in cultured rodent hippocampal neurons. Δex6 but not C31R mutation leads to IL1RAPL1 protein instability and mislocalization within dendrites. Analysis of different markers of excitatory synapses and sEPSC recording revealed that both mutants fail to induce pre- and post-synaptic differentiation, contrary to WT IL1RAPL1 protein. Cell aggregation and immunoprecipitation assays in HEK293 cells showed a reduction of the interaction between IL1RAPL1 mutants and PTPδ that could explain the observed synaptogenic defect in neurons. However, these mutants do not affect all cellular signaling because their over-expression still activates JNK pathway. We conclude that both mutations described in this study lead to a partial loss of function of the IL1RAPL1 protein through different mechanisms. Our work highlights the important function of the trans-synaptic PTPδ/IL1RAPL1 interaction in synaptogenesis and as such in ID in the patients. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.