Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2

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Pekkinen , M , Terhal , P A , Botto , L D , Henning , P , Mäkitie , R E , Roschger , P , Jain , A , Kol , M , Kjellberg , M A , Paschalis , E P , van Gassen , K , Murray , M , Bayrak-Toydemir , P , Magnusson , M K , Jans , J , Kausar , M , Carey , J C , Somerharju , P , Lerner , U H , Olkkonen , V M , Klaushofer , K , Holthuis , J C M & Mäkitie , O 2019 , ' Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2 ' , JCI INSIGHT , vol. 4 , no. 7 , 126180 . https://doi.org/10.1172/jci.insight.126180

Title: Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2
Author: Pekkinen, Minna; Terhal, Paulien A.; Botto, Lorenzo D.; Henning, Petra; Mäkitie, Riikka E.; Roschger, Paul; Jain, Amrita; Kol, Matthijs; Kjellberg, Matti A.; Paschalis, Eleftherios P.; van Gassen, Koen; Murray, Mary; Bayrak-Toydemir, Pinar; Magnusson, Maria K.; Jans, Judith; Kausar, Mehran; Carey, John C.; Somerharju, Pentti; Lerner, Ulf H.; Olkkonen, Vesa M.; Klaushofer, Klaus; Holthuis, Joost C. M.; Mäkitie, Outi
Contributor organization: Clinicum
Faculty of Medicine
CAMM - Research Program for Clinical and Molecular Metabolism
University of Helsinki
Children's Hospital
Research Programs Unit
Department of Biochemistry and Developmental Biology
Department of Anatomy
Lastentautien yksikkö
HUS Children and Adolescents
HUS Internal Medicine and Rehabilitation
Date: 2019-04-04
Language: eng
Number of pages: 20
Belongs to series: JCI INSIGHT
ISSN: 2379-3708
DOI: https://doi.org/10.1172/jci.insight.126180
URI: http://hdl.handle.net/10138/301402
Abstract: Mechanisms leading to osteoporosis are incompletely understood. Genetic disorders with skeletal fragility provide insight into metabolic pathways contributing to bone strength. We evaluated 6 families with rare skeletal phenotypes and osteoporosis by next-generation sequencing. In all the families, we identified a heterozygous variant in SGMS2, a gene prominently expressed in cortical bone and encoding the plasma membrane-resident sphingomyelin synthase SMS2. Four unrelated families shared the same nonsense variant, c.148C>T (p.Arg50*), whereas the other families had a missense variant, c.185T>G (p.IIe62Ser) or c.191T>G (p.Met64Arg). Subjects with p.Arg50* presented with childhood-onset osteoporosis with or without cranial sclerosis. Patients with p.IIe62Ser or p.Met64Arg had a more severe presentation, with neonatal fractures, severe short stature, and spondylometaphyseal dysplasial Several subjects had experienced peripheral facial nerve palsy or other neurological manifestations. Bone biopsies showed markedly altered bone material characteristics, including defective bone mineralization. Osteoclast formation and function in vitro was normal. While the p.Arg50* mutation yielded a catalytically inactive enzyme, p.IIe62Ser and p.Met64Arg each enhanced the rate of de novo sphingomyelin production by blocking export of a functional enzyme from the endoplasmic reticulum. SGMS2 pathogenic variants underlie a spectrum of skeletal conditions, ranging from isolated osteoporosis to complex skeletal dysplasia, suggesting a critical role for plasma membrane-bound sphingomyelin metabolism in skeletal homeostasis.
3111 Biomedicine
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion

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