Molecular Mech Anisms Of SNX27^p.R198W Mutation In The Pathogenesis Of Intellectual Disability

As a member of sorting nexin family,sorting nexin 27(SNX27)plays an important role in regulating intracellular protein trafficking and signal transduction.Abberant expression of SNX27 has been reported in Alzheimer's disease(AD)and Down's syndrome(DS).In addition,the absence of SNX27 has been shown to lead to severe neurodevelopmental diseases.A rare missense mutation on SNX27 gene 592C>T(equivalent to amino acid R198W)has been identified in patients with mental retardation,however,it remains unclear whether and how the mutation causes intellectual disability.As SNX27R198 was located in the conserved structural domain of SNX27-PX domain,we were wondering whether SNX27p R19sW mutation affects the interaction between SNX27-PX domain and phosphatidylinositol-3-phosphate(PI(3)P),which is highly enriched in early endosomes.Using a lipid binding assay and an immunocytochemical assay,we found that SNX27p.R198W mutation disrupts the SNX27-PI(3)P interaction and endosomal localization of SNX27.In order to examine functions of SNX27p R198W in vivo,we generated a SNX27p.R196W(equivalent to human 8198)knockin mouse,and evaluated the phenotypes of the mutant mice using a combination of behavioral,morphological and electrophysiological techaniques.We found that homozygous mutant mice(Snx27KI/KI)display developmental retardation and lower survival rate.In addition,we found a reduced density of mature dendritic spines,and impaired learning and memory,indicating SNX27p.R198W mutation is pathogenic.RNAseq analysis indicates dysregulation of mitochondrial function and energy metabolism-related genes in the hippocampi of Snx27KI/KI mice.In summary,we generated a novel animal research model of intellectual disability SNX27R196W knockin mice.This study indicates a crucial role of SNX27 in learning and memory.In addition,the study suggests a possibility of SNX27 related molecular network as a therapeutic target for intellectual disability.