An intellectual-disability-associated mutation of the transcriptional regulator NACC1 impairs glutamatergic neurotransmission

Advances in genome sequencing technologies have favored the identification of rare de novo mutations linked to neurological disorders humans. Recently, a autosomal dominant mutation NACC1 was identified (NM_052876.3: c.892C > T, NP_443108.1; p.Arg298Trp), associated with severe symptoms including intellectual disability, microcephaly, and epilepsy. As had never before been diseases, we investigated how this might lead altered brain function. We examined neurotransmission autaptic glutamatergic mouse neurons expressing murine homolog human mutant NACC1, i.e., Nacc1-R284W. observed that expression Nacc1-R284W impaired cell-autonomous manner, likely through negative mechanism. Furthermore, by screening for Nacc1 interaction targets brain, SynGAP1, GluK2A, several SUMO E3 ligases as novel partners. At biochemical level, exhibited reduced binding SynGAP1 also showed greatly increased SUMOylation. Ablating SUMOylation partially restored its but did not restore GluK2A. Overall, these data indicate role regulating neurotransmission, which is substantially disease-associated mutant. This study provides first functional insights into potential deficits neuronal function patients protein.