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Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2
Minna Pekkinen, … , Joost C.M. Holthuis, Outi Mäkitie
Minna Pekkinen, … , Joost C.M. Holthuis, Outi Mäkitie
Published February 19, 2019
Citation Information: JCI Insight. 2019;4(7):e126180. https://doi.org/10.1172/jci.insight.126180.
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Research Article Endocrinology Genetics

Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2

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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.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.

Authors

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, Vesa M. Olkkonen, Klaus Klaushofer, Joost C.M. Holthuis, Outi Mäkitie

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Figure 4

Bone tissue characteristics.

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Bone tissue characteristics.
(A) Quantitative backscatter electron imagi...
(A) Quantitative backscatter electron imaging (qBEI) of the transiliac bone biopsy samples. Top: There is no clear separation between the trabecular and cortical compartment. Pixel gray levels correspond to mineral content (bright to higher and dark to lower). Scale bars: 200 μm; 100 μm (zoom). Nonmineralized Sharpey’s fibres are infusing the cortex (solid white arrows, zoomed-in areas), clearly identified by polarized light microscopy (see C). Bottom: Bone mineralization density distribution (BMDD) curves for the 2 patients. Ref, reference BMDD for children (66). BMDD for cancellous bone showed reduced mineral content, increased heterogeneity in matrix mineralization, and highly increased portion of lowly mineralized bone. In cortical bone of patient F1-1, the BMDD showed a peak shift to higher mineralization due to increased proportion of primary bone mineralized to a higher extent. In patient F2-1, the cortical bone mineralization was overall reduced. (B) Confocal laser scanning microscopy (CLSM) of fluorescence labeled bone. Left: CLSM image of a mineralizing surface shows diffuse appearance of double labeling. Right: Corresponding qBEI image (identical bone area; scale bar: 200 μm). Of note, the osteocyte lacunae are enlarged and of abnormal shape. (C-E) Polarized light microscopy of the bone samples. Paired images of bright-field (right) and linear polarized (left) light (scale bars: 100 μm). (C) Cortical detail of patient F1-1 (region close to zoomed-in area of A): predominantly woven bone infused with Sharpey’s fibres (thin white and black arrows) and bone formation (thick empty black and white arrows) and resorption (thick black arrow in C and thick empty white arrows in A). Of note, the new osteoid does not show a lamellar fibril arrangement. (D and E) Examples of bone tissue with coexisting woven and lamellar bone matrix. Of note, an osteon (arrows) has woven character in the center though at the peripheral region it is lamellar.

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