Relevance to Autism

LRRC7-knockout mice show changes in the protein content of the postsynaptic density and exhibit impaired short-term and spatial memory, increased anxiety and aggression, and abnormal motor behavior (Carlisle et al., 2011). De novo loss-of-function (LoF) variant in LRRC7 have also been identified in ASD probands (Yuen et al., 2015; Zhou et al., 2022). More recently, Willim et al., 2024 identified 33 individuals (one of them previously described) with a dominant neurodevelopmental disorder caused by heterozygous missense or loss-of-function variants in LRRC7 that was characterized by intellectual disability, autism, ADHD, aggression and, in several cases, hyperphagia-associated obesity. Moreover, Willim et al., 2024 found that a variant in the PDZ domain of LRRC7 interfered with synaptic targeting of Densin-180 (the protein encoded by LRRC7) in primary cultured neurons, while variants in the LRR domain impaired binding of Densin-180 to newly identified candidate binding partners.

Molecular Function

Required for normal synaptic spine architecture and function. Necessary for DISC1 and GRM5 localization to postsynaptic density complexes and for both N-methyl D-aspartate receptor-dependent and metabotropic glutamate receptor-dependent long term depression.

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Model Summary

Densin influences the function of mGluRs and CaMKII at synapses and contributes to localization of mGluR5 and DISC1 in the PSD fraction.

References