Disease-related PSS1 mutant impedes the formation and function of osteoclasts.

Phosphatidylserine (PS) is an acidic phospholipid that is involved in various cellular events. Heterologous dominant mutations have been identified in the gene encoding PS synthase 1 (PSS1) in patients with a congenital disease called Lenz-Majewski syndrome (LMS). LMS patients show various symptoms, including craniofacial/distal-limb bone dysplasia and progressive hyperostosis. The LMS-causing gain-of-function mutants of PSS1 (PSS1) have been shown to synthesize PS without control, but why the uncontrolled synthesis would lead to LMS is unknown. Here we investigated the effect of PSS1 on osteoclasts (OCs) to elucidate the causative mechanism of LMS. PSS1 did not affect the expression of OC-related genes, but inhibited the formation, multinucleation, and activity of OCs. Especially, OCs expressing PSS1 showed abnormal patterns and dynamics of actin podosome clusters, which have roles in OC migration and fusion. PSS1 did not affect the level of PS but changed the acyl chain compositions of PS and phosphatidylethanolamine, and decreased the level of phosphatidylinositol. Introduction of a catalytically-inactive mutation into PSS cancelled the changes in phospholipids and the phenotypes observed in OCs expressing PSS1. A gain-of-function mutant of PSS2 (PSS2 R97K) also impaired OC formation and caused changes in phospholipid composition similar to the changes caused by PSS1. Our results suggest that uncontrolled PS synthesis by PSS1 causes changes in the quantity or fatty acid composition of certain phospholipid classes, impairing OC formation and function, which might be a cause of osteosclerosis in LMS patients.