Inactivation of spermine synthase in mice causes osteopenia due to reduced osteoblast activity.

This article focuses on the role of spermine synthase (SMS), encoded by the SMS gene, in bone remodeling and its involvement in Snyder–Robinson syndrome (SRS), an X-linked recessive disorder characterized by intellectual disability, muscular hypotonia, infertility, and skeletal abnormalities including osteoporosis. The study reports clinical findings from two male patients with pathogenic or likely pathogenic SMS variants presenting osteoporosis and uses a newly developed mouse model harboring the SMS p.G56S variant to investigate skeletal effects. The SMSG56S/0 mice exhibited reduced bone mass, decreased cortical thickness, impaired mechanical bone properties, and a lowered bone formation rate due to diminished osteoblast activity, supported by ex vivo evidence of defective osteoblast mineralization. These findings establish SMS as physiologically relevant for osteoblast function and bone formation, providing a validated model to further explore SRS pathomechanisms and potential therapeutic approaches.