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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). Patients with LMS show various symp...

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Autores principales: Sugahara, Sari, Ishino, Yuki, Sawada, Koki, Iwata, Tsumugi, Shimanaka, Yuta, Aoki, Junken, Arai, Hiroyuki, Kono, Nozomu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10641532/
https://www.ncbi.nlm.nih.gov/pubmed/37714410
http://dx.doi.org/10.1016/j.jlr.2023.100443
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author Sugahara, Sari
Ishino, Yuki
Sawada, Koki
Iwata, Tsumugi
Shimanaka, Yuta
Aoki, Junken
Arai, Hiroyuki
Kono, Nozomu
author_facet Sugahara, Sari
Ishino, Yuki
Sawada, Koki
Iwata, Tsumugi
Shimanaka, Yuta
Aoki, Junken
Arai, Hiroyuki
Kono, Nozomu
author_sort Sugahara, Sari
collection PubMed
description 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). Patients with LMS show various symptoms, including craniofacial/distal-limb bone dysplasia and progressive hyperostosis. The LMS-causing gain-of-function mutants of PSS1 (PSS1(LMS)) 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(LMS) on osteoclasts (OCs) to elucidate the causative mechanism of LMS. PSS1(LMS) did not affect the expression of OC-related genes but inhibited the formation, multinucleation, and activity of OCs. Especially, OCs expressing PSS1(LMS) showed abnormal patterns and dynamics of actin podosome clusters, which have roles in OC migration and fusion. PSS1(LMS) did not affect the level of PS but changed the acyl chain compositions of PS and phosphatidylethanolamine, and decreased the level of phosphatidylinositol. The introduction of a catalytically inactive mutation into PSS(LMS) canceled the changes in phospholipids and the phenotypes observed in OCs expressing PSS1(LMS). 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(LMS). Our results suggest that uncontrolled PS synthesis by PSS1(LMS) 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 patients with LMS.
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spelling pubmed-106415322023-11-14 Disease-related PSS1 mutant impedes the formation and function of osteoclasts Sugahara, Sari Ishino, Yuki Sawada, Koki Iwata, Tsumugi Shimanaka, Yuta Aoki, Junken Arai, Hiroyuki Kono, Nozomu J Lipid Res Research Article 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). Patients with LMS show various symptoms, including craniofacial/distal-limb bone dysplasia and progressive hyperostosis. The LMS-causing gain-of-function mutants of PSS1 (PSS1(LMS)) 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(LMS) on osteoclasts (OCs) to elucidate the causative mechanism of LMS. PSS1(LMS) did not affect the expression of OC-related genes but inhibited the formation, multinucleation, and activity of OCs. Especially, OCs expressing PSS1(LMS) showed abnormal patterns and dynamics of actin podosome clusters, which have roles in OC migration and fusion. PSS1(LMS) did not affect the level of PS but changed the acyl chain compositions of PS and phosphatidylethanolamine, and decreased the level of phosphatidylinositol. The introduction of a catalytically inactive mutation into PSS(LMS) canceled the changes in phospholipids and the phenotypes observed in OCs expressing PSS1(LMS). 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(LMS). Our results suggest that uncontrolled PS synthesis by PSS1(LMS) 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 patients with LMS. American Society for Biochemistry and Molecular Biology 2023-09-14 /pmc/articles/PMC10641532/ /pubmed/37714410 http://dx.doi.org/10.1016/j.jlr.2023.100443 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Sugahara, Sari
Ishino, Yuki
Sawada, Koki
Iwata, Tsumugi
Shimanaka, Yuta
Aoki, Junken
Arai, Hiroyuki
Kono, Nozomu
Disease-related PSS1 mutant impedes the formation and function of osteoclasts
title Disease-related PSS1 mutant impedes the formation and function of osteoclasts
title_full Disease-related PSS1 mutant impedes the formation and function of osteoclasts
title_fullStr Disease-related PSS1 mutant impedes the formation and function of osteoclasts
title_full_unstemmed Disease-related PSS1 mutant impedes the formation and function of osteoclasts
title_short Disease-related PSS1 mutant impedes the formation and function of osteoclasts
title_sort disease-related pss1 mutant impedes the formation and function of osteoclasts
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10641532/
https://www.ncbi.nlm.nih.gov/pubmed/37714410
http://dx.doi.org/10.1016/j.jlr.2023.100443
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