دورية أكاديمية
Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2.
| العنوان: | Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2. |
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| المؤلفون: | Pekkinen M; 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., Terhal PA; Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands., Botto LD; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA., Henning P; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden., Mäkitie RE; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland, and Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland., Roschger P; Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria., Jain A; Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, Osnabrück, Germany., Kol M; Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, Osnabrück, Germany., Kjellberg MA; Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Paschalis EP; Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria., van Gassen K; Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands., Murray M; Division of Pediatric Endocrinology & Diabetes, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA., Bayrak-Toydemir P; Department of Pathology, University of Utah, Salt Lake City, Utah, USA, and ARUP Laboratories, Salt Lake City, Utah, USA., Magnusson MK; Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden., Jans J; Laboratory of Metabolic Diseases, University Medical Center Utrecht, Utrecht, Netherlands., Kausar M; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland, and Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland., Carey JC; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA., Somerharju P; Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Lerner UH; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden., Olkkonen VM; Minerva Foundation Institute for Medical Research, Biomedicum, Helsinki, Finland, and Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki,Finland., Klaushofer K; Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria., Holthuis JC; Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, Osnabrück, Germany.; Biochemistry and Biophysics Division, Bijvoet Center and Institute of Biomembranes, Utrecht University, Utrecht, Netherlands., Mäkitie O; 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 Molecular Medicine and Surgery, Karolinska Institutet, and Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden. |
| المصدر: | JCI insight [JCI Insight] 2019 Apr 04; Vol. 4 (7). Date of Electronic Publication: 2019 Apr 04 (Print Publication: 2019). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: eCollection Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]- |
| مواضيع طبية MeSH: | Calcification, Physiologic/*genetics , Membrane Proteins/*genetics , Nerve Tissue Proteins/*genetics , Osteochondrodysplasias/*genetics , Osteoporosis/*genetics , Transferases (Other Substituted Phosphate Groups)/*genetics, Adult ; Age of Onset ; Aged, 80 and over ; Bone and Bones/diagnostic imaging ; Bone and Bones/pathology ; Child ; Child, Preschool ; DNA Mutational Analysis ; Female ; Heterozygote ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Mutation, Missense ; Osteochondrodysplasias/diagnosis ; Osteochondrodysplasias/pathology ; Osteoporosis/diagnosis ; Osteoporosis/pathology ; Pedigree ; Young Adult |
| مستخلص: | 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. |
| References: | Nat Mater. 2006 Jan;5(1):52-5. (PMID: 16341218) J Biol Chem. 2006 Oct 6;281(40):29421-5. (PMID: 16905542) Dev Cell. 2007 Jan;12(1):113-27. (PMID: 17199045) Bone. 2008 Mar;42(3):456-66. (PMID: 18096457) Calcif Tissue Int. 2015 Sep;97(3):201-12. (PMID: 25772807) N Engl J Med. 2016 Jan 21;374(3):254-62. (PMID: 26789873) Mol Cell Biol. 2011 Oct;31(20):4205-18. (PMID: 21844222) J Lipid Res. 2016 Mar;57(3):388-97. (PMID: 26733148) Gigascience. 2013 Jun 25;2(1):9. (PMID: 23800020) J Inherit Metab Dis. 2015 Jan;38(1):99-110. (PMID: 25178427) Biochem Biophys Res Commun. 2012 Jan 20;417(3):1014-7. (PMID: 22209789) J Bone Miner Res. 2011 Aug;26(8):1748-58. (PMID: 21351145) Ann Rheum Dis. 2019 Jan;78(1):100-110. (PMID: 30026257) Radiology. 1976 May;119(2):385-7. (PMID: 1265267) J Struct Biol. 2011 Feb;173(2):303-11. (PMID: 21081167) Pharmacol Rev. 2008 Jun;60(2):181-95. (PMID: 18552276) Am J Med Genet A. 2015 Dec;167A(12):2869-92. (PMID: 26394607) Cell Mol Life Sci. 2015 Mar;72(5):959-69. (PMID: 25424644) Genome Res. 2010 Sep;20(9):1297-303. (PMID: 20644199) Trends Cell Biol. 2012 Jan;22(1):50-60. (PMID: 22001186) J Biol Chem. 2011 Aug 12;286(32):28544-55. (PMID: 21669879) J Bone Miner Res. 2011 Feb;26(2):286-97. (PMID: 20684022) Bone. 2007 May;40(5):1308-19. (PMID: 17337263) Am J Hum Genet. 2014 Jan 2;94(1):105-12. (PMID: 24387990) Orphanet J Rare Dis. 2017 Feb 23;12(1):41. (PMID: 28228103) Am J Med Genet. 2001 Mar 15;99(3):238-43. (PMID: 11241496) J Biol Chem. 1957 May;226(1):497-509. (PMID: 13428781) Nature. 1990 May 31;345(6274):442-4. (PMID: 2188141) EMBO J. 2004 Jan 14;23(1):33-44. (PMID: 14685263) Skeletal Radiol. 1996 Nov;25(8):717-22. (PMID: 8958616) Nucleic Acids Res. 2010 Sep;38(16):e164. (PMID: 20601685) Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4314-9. (PMID: 27044099) Anal Chem. 2006 Dec 15;78(24):8324-31. (PMID: 17165823) J Bone Miner Res. 2007 Apr;22(4):617-27. (PMID: 17227223) Bone. 2000 Feb;26(2):103-9. (PMID: 10678403) Nat Genet. 2011 May;43(5):491-8. (PMID: 21478889) J Bone Miner Res. 2017 Sep;32(9):1884-1892. (PMID: 28548288) iScience. 2018 Oct 26;8:250-266. (PMID: 30343189) Trends Endocrinol Metab. 2016 May;27(5):262-281. (PMID: 27079517) J Bone Miner Res. 1999 Jan;14(1):32-8. (PMID: 9893063) Nat Genet. 2005 Aug;37(8):803-5. (PMID: 16025116) Nat Genet. 2014 Jan;46(1):70-6. (PMID: 24241535) Nucleic Acids Res. 2001 May 1;29(9):e45. (PMID: 11328886) J Biol Chem. 2017 Jan 20;292(3):1122-1141. (PMID: 27927984) J Cell Biol. 2015 Jan 5;208(1):125-36. (PMID: 25547154) Immunol Invest. 2013;42(7):555-622. (PMID: 24004059) Bone. 1998 Oct;23(4):319-26. (PMID: 9763143) J Cell Biol. 2011 Jul 25;194(2):277-89. (PMID: 21788370) Nat Med. 2018 May;24(5):667-678. (PMID: 29662200) Am J Med Genet A. 2009 Nov;149A(11):2371-7. (PMID: 19839042) J Clin Densitom. 1999 Spring;2(1):45-53. (PMID: 23547313) Sci Rep. 2017 Aug 21;7(1):8935. (PMID: 28827734) J Bone Miner Res. 2012 May;27(5):1142-9. (PMID: 22258757) Methods. 2001 Dec;25(4):402-8. (PMID: 11846609) Hum Mutat. 2015 Oct;36(10):928-30. (PMID: 26220891) Genome Biol. 2011 Sep 28;12(9):R94. (PMID: 21955854) Am J Roentgenol Radium Ther Nucl Med. 1974 May;121(1):121-3. (PMID: 4833899) N Engl J Med. 2013 May 9;368(19):1809-16. (PMID: 23656646) Curr Protoc Bioinformatics. 2013;43:11.10.1-11.10.33. (PMID: 25431634) J Cell Sci. 2017 Jan 15;130(2):360-371. (PMID: 27888218) Bone. 2009 Jun;44(6):1043-8. (PMID: 19268565) Blood. 2002 Jan 1;99(1):111-20. (PMID: 11756160) J Biol Chem. 1993 May 5;268(13):9901-7. (PMID: 8486670) |
| معلومات مُعتمدة: | UL1 TR002538 United States TR NCATS NIH HHS |
| فهرسة مساهمة: | Keywords: Bone disease; Endocrinology; Genetic diseases; Genetics; Osteoporosis |
| المشرفين على المادة: | 0 (Membrane Proteins) 0 (Nerve Tissue Proteins) EC 2.7.8.- (SGMS1 protein, human) EC 2.7.8.- (Transferases (Other Substituted Phosphate Groups)) |
| تواريخ الأحداث: | Date Created: 20190220 Date Completed: 20200629 Latest Revision: 20211120 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC6483641 |
| DOI: | 10.1172/jci.insight.126180 |
| PMID: | 30779713 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 2379-3708 |
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| DOI: | 10.1172/jci.insight.126180 |