ArticleJCI insight2019
Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2.
Article in JCI insight, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 81 citations in OpenAlex.
- Cumulative microscopy reveals cellular states in fibroblasts from patients with genetic disorders.EMBO reports · 2026Article
- Human growth plates house resting zone sub-populations with features of quiescent stem cells.Bone research · 2026Article
- PathogenicFrontiers in endocrinology · 2026Article
- A distinct serum metabolic profile characterizes osteosarcopenia: identifying potential metabolic biomarkers.Frontiers in endocrinology · 2026Observational
- Spectrum of Osteoporosis Etiologies with Associated Vertebral Compression Fractures in Children: Analysis of 11 Cases.Journal of clinical medicine · 2025Article
- Metabolic signatures in osteoporotic cancellous bone: a comprehensive dual-platform metabolomic analysis.BMC musculoskeletal disorders · 2025Article
- Integrative Single-Cell and Machine Learning Analysis Develops a Glutamine Metabolism-Based Prognostic Model and Identifies MSMO1 as a Therapeutic Target in Osteosarcoma.Biomolecules · 2025Article
- Utilizing CRISPR-Cas13d-knockdown in zebrafish to study a rare monogenic bone fragility syndrome.JBMR plus · 2025Article
- Transcriptomic and lipidomic profiling provide novel insight into the pathogenesis of monogenicJBMR plus · 2025Article
- Article
- A novel SGMS2 mutation associated with high bone mass; description of an affected family with recurrent fragility fractures.Bone reports · 2025Article
- Combining untargeted and targeted metabolomic profiling reveals principal differences between osteopenia, Osteoporosis and healthy controls.Aging clinical and experimental research · 2025Article
- Human genetic defects of sphingolipid synthesis.Journal of inherited metabolic disease · 2025Review
- Article
- A Dyadic Nosology for Osteogenesis Imperfecta and Bone Fragility Syndromes 2024.Calcified tissue international · 2024Review
- Regulation of cellular and systemic sphingolipid homeostasis.Nature reviews. Molecular cell biology · 2024Review
- Sphingolipid-Induced Bone Regulation and Its Emerging Role in Dysfunction Due to Disease and Infection.International journal of molecular sciences · 2024Review
- Role of gene interactions in the pathophysiology of skeletal dysplasias: A case report in Colombia.Journal, genetic engineering & biotechnology · 2024Article
- Bone fragility and osteoporosis in children and young adults.Journal of endocrinological investigation · 2024Review
- Sorting of complex sphingolipids within the cellular endomembrane systems.Frontiers in cell and developmental biology · 2024Review
Corrections and comments
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Authors and funding
23 authors at 11 institutions in 6 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.