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JCI Insight. 2019 Apr 4;4(7). pii: 126180. doi: 10.1172/jci.insight.126180. eCollection 2019 Apr 4.

Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2.

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Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland, and Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland.
Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands.
Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria.
Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, Osnabrück, Germany.
Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Division of Pediatric Endocrinology & Diabetes, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
Department of Pathology, University of Utah, Salt Lake City, Utah, USA, and ARUP Laboratories, Salt Lake City, Utah, USA.
Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Laboratory of Metabolic Diseases, University Medical Center Utrecht, Utrecht, Netherlands.
Minerva Foundation Institute for Medical Research, Biomedicum, Helsinki, Finland, and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki,Finland.
Biochemistry and Biophysics Division, Bijvoet Center and Institute of Biomembranes, Utrecht University, Utrecht, Netherlands.
Department of Molecular Medicine and Surgery, Karolinska Institutet, and Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden.


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.


Bone disease; Endocrinology; Genetic diseases; Genetics; Osteoporosis

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