Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Mutations in the interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene are linked to intellectual disability (ID) and autism spectrum disorder.
• IL1RAPL1 protein plays a crucial role in the formation and function of excitatory synapses by interacting with synaptic partners like PSD-95 and PTPδ.

Purpose of the Study:

• To investigate the synaptic consequences of three IL1RAPL1 mutations (two novel deletions of exon 6 [Δex6] and one point mutation [C31R]) found in patients with ID.
• To characterize the impact of these mutations on synapse formation, protein stability, and interactions with synaptic partners.

Main Methods:

• Over-expression of wild-type (WT) and mutant IL1RAPL1 in cultured rodent hippocampal neurons.
• Immunofluorescence microscopy to analyze synapse markers and protein localization.
• Electrophysiological recordings (sEPSC) to assess synaptic function.
• Cell aggregation and immunoprecipitation assays in HEK293 cells to study protein interactions.

Main Results:

• The Δex6 mutation caused IL1RAPL1 protein instability and mislocalization, while the C31R mutation did not.
• Both IL1RAPL1 mutants impaired pre- and post-synaptic differentiation, unlike WT IL1RAPL1.
• Mutant IL1RAPL1 showed reduced interaction with PTPδ, explaining the synaptogenic defect.
• Over-expression of mutants still activated the JNK pathway, indicating partial loss of function.

Conclusions:

• Both studied IL1RAPL1 mutations lead to a partial loss of function, affecting synaptogenesis through distinct mechanisms.
• The trans-synaptic PTPδ/IL1RAPL1 interaction is critical for synaptogenesis and implicated in ID.
• Understanding these mechanisms provides insights into the genetic basis of intellectual disability.