Snyder-Robinson Syndrome (SRS) is a rare X-linked recessive disorder caused by a mutation in the SMS gene encoding spermine synthase and aberrant polyamine metabolism. SRS is characterized by intellectual disability, thin habitus, seizure, low muscle tone/hypotonia, and osteoporosis. Progress towards understanding and treating SRS requires a model that recapitulates human mutations and disease presentations. Here, we evaluated molecular and neurological presentations in the G56S mouse model carrying a missense mutation in the Sms gene. The lack of SMS protein in the G56S mice resulted in increased spermidine/spermine ratio, failure to thrive, short stature, and reduced bone density. They showed impaired learning capacity, increased anxiety, reduced mobility, and heightened fear responses, accompanied by reduced total and regional brain volumes. Furthermore, impaired mitochondrial oxidative phosphorylation was evident in G56S cerebral cortex, G56S fibroblasts, and Sms-null hippocampal cells, and may serve as a future therapeutic target. Collectively, our study establishes the suitability of the G56S mice as a preclinical model for SRS and provides a set of molecular and functional outcome measures that can be used to evaluate therapeutic interventions for SRS.
Keywords: Mouse model; Neurological functions; Pathogenesis; Rare disease; Spermine; Spermine synthase.
© 2024. Published by The Company of Biologists Ltd.