Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2

Autor(en): Pekkinen, Minna
Terhal, Paulien A.
Botto, Lorenzo D.
Henning, Petra
Makitie, Riikka E.
Roschger, Paul
Jain, Amrita
Kol, Matthijs
Kjellberg, Matti A.
Paschalis, Eleftherios P.
van Lassen, 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.
Makitie, Outi
Stichwörter: CALVARIAL DOUGHNUT LESIONS; Medicine, Research & Experimental; METABOLISM; MINERALIZATION DENSITY DISTRIBUTION; MUTATIONS; NORMATIVE DATA; OSTEOGENESIS; OSTEOPETROSIS; RELATIVE QUANTIFICATION; Research & Experimental Medicine; SPHINGOMYELIN; SPHINGOSINE-1-PHOSPHATE
Erscheinungsdatum: 2019
Herausgeber: AMER SOC CLINICAL INVESTIGATION INC
Enthalten in: JCI INSIGHT
Band: 4
Ausgabe: 7
Zusammenfassung: 
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.
DOI: 10.1172/jci.insight.126180

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