Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2

Minna Pekkinen, Paulien A Terhal, Lorenzo D Botto, Petra Henning, Riikka E Mäkitie, Paul Roschger, Amrita Jain, Matthijs Kol, Matti A Kjellberg, Eleftherios P Paschalis, Koen van Gassen, Mary Murray, Pinar Bayrak-Toydemir, Maria K Magnusson, Judith Jans, Mehran Kausar, John C Carey, Pentti Somerharju, Ulf H Lerner, Olkkonen M VesaKlaus Klaushofer, Joost Cm Holthuis, Outi Mäkitie

Research output: Contribution to journalArticleAcademicpeer-review


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.Ile62Ser) or c.191T>G (p.Met64Arg). Subjects with p.Arg50* presented with childhood-onset osteoporosis with or without cranial sclerosis. Patients with p.Ile62Ser or p.Met64Arg had a more severe presentation, with neonatal fractures, severe short stature, and spondylometaphyseal dysplasia. 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.Ile62Ser 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.

Original languageEnglish
Article numbere126180
Number of pages21
JournalJCI Insight
Issue number7
Early online date19 Feb 2019
Publication statusPublished - 4 Apr 2019


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