Truncating mutations in SHANK3 associated with global developmental delay interfere with nuclear β‐catenin signaling

AbstractMutations inSHANK3, coding for a large scaffold protein of excitatory synapses in the CNS, are associated with neurodevelopmental disorders including autism spectrum disorders (ASDs) and intellectual disability (ID). Several cases have been identified in which the mutation leads to truncation of the protein, eliminating C ‐terminal sequences required for postsynaptic targeting of the protein. We identify here a patient with a truncating mutation inSHANK3, affected by severe global developmental delay and intellectual disability. By analyzing the subcellular distribution of this truncated form of Shank3, we identified a nuclear localization signal (NLS) in the N ‐terminal part of the protein which is responsible for targeting Shank3 fragments to the nucleus. To determine the relevance of Shank3 for nuclear signaling, we analyze how it affects signaling by β‐catenin, a component of the Wnt pathway. We show that full length as well as truncated variants of Shank3 interact with β‐catenin via the PDZ domain of Shank3, and the armadillo repeats of β‐catenin. As a result of this interaction, truncated forms of Shank3 and β‐catenin strictly colocalize in small intranuclear bodies both in 293T cells and in rat hippocampal neurons. On a functiona l level, the sequestration of both proteins in these nuclear bodies is associated with a strongly repressed transcriptional activation by β‐catenin, due to interaction with the truncated Shank3 fragment found in pati...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research