Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis

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

来源：Human Molecular Genetics, 2015, 24(4): 1106-1118.

DOI：10.1093/hmg/ddu523

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 PTP delta, 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 (Delta ex6) 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. Delta ex6 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 PTP delta 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 transsynaptic PTP delta/IL1RAPL1 interaction in synaptogenesis and as such in ID in the patients.

• 出版日期2015-2-15