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  • Pekkinen, M. (author)

Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2

  • Article/chapterEnglish2019

Publisher, publication year, extent ...

  • 2019-04-04
  • American Society for Clinical Investigation,2019

Numbers

  • LIBRIS-ID:oai:gup.ub.gu.se/280026
  • https://gup.ub.gu.se/publication/280026URI
  • https://doi.org/10.1172/jci.insight.126180DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:140641603URI

Supplementary language notes

  • Language:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

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  • Terhal, P. A. (author)
  • Botto, L. D. (author)
  • Henning, Petra,1974Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Centre for Bone and Arthritis Research,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition(Swepub:gu)xhenpe (author)
  • Makitie, R. E. (author)
  • Roschger, P. (author)
  • Jain, A. (author)
  • Magnusson, Maria K,1972Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi,Institute of Biomedicine, Department of Microbiology and Immunology(Swepub:gu)xmmara (author)
  • Kjellberg, M. A. (author)
  • Paschalis, E. P. (author)
  • van Lassen, K. (author)
  • Murray, M. (author)
  • Bayrak-Toydemir, P. (author)
  • Magnusson, Maria K,1972Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi,Institute of Biomedicine, Department of Microbiology and Immunology(Swepub:gu)xmmara (author)
  • Jans, J. (author)
  • Kausar, M. (author)
  • Carey, J. C. (author)
  • Somerharju, P. (author)
  • Lerner, Ulf HGothenburg University,Göteborgs universitet,Centre for Bone and Arthritis Research,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition(Swepub:gu)xlerul (author)
  • Olkkonen, V. M.Karolinska Institutet (author)
  • Klaushofer, K. (author)
  • Holthuis, J. C. M. (author)
  • Makitie, O. (author)
  • Göteborgs universitetInstitutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition (creator_code:org_t)

Related titles

  • In:Jci Insight: American Society for Clinical Investigation4:72379-3708

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