An improved Sms p.Gly56Ser model of Snyder-Robinson syndrome reveals phenotypic parallels with clinical features.

Snyder-Robinson syndrome (SRS) is a rare X-linked disorder, caused by pathogenic variants in spermine synthase (SMS), associated with spermine deficiency and excessive spermidine accumulation. Previously reported mouse models exhibited reduced birthrate and survival of affected males, greatly limiting their experimental utility. Here, we describe a new mouse model, carrying the clinically relevant Sms p.Gly56Ser (SmsG56S) allele, in which viable males are recovered at Mendelian ratios, enabling generation of adequately powered cohorts. Hemizygous males produced markedly reduced SMS protein across tissues, recreating the biochemical hallmark of SRS, an elevated spermidine:spermine ratio. SmsG56S/Y males exhibited reduced body size, altered body composition, decreased locomotor and exploratory behaviors, and reduced seizure threshold, aligning with clinical features reported in patients with SRS. Serum low-density lipoprotein, high-density lipoprotein and cholesterol levels were reduced, while brain histology revealed modest region-specific astrocytic changes. Comprehensive polyamine profiling revealed tissue-specific biochemical disturbances, highlighting putrescine elevation in the brain and informing the development of translational strategies and windows for intervention. Overall, this improved model reproduces multiple key aspects of the human SRS phenotype and provides a robust platform for mechanistic studies and preclinical evaluation of therapies.