Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2

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.

Genome-Wide Analysis Reveals Human-Mediated Introgression from Western Pigs to Indigenous Chinese Breeds

“…These are associated with several important traits. For example, REG3G, IER3, SGMS2, and DKK2 [52][53][54][55] are involved in skeletal development, TNXB [56] in muscle growth, CH25H, DRG1 [57,58] in digestive secretion, and NGLY [59] in vision. The genes OXSM and NGLY are also located in regions affected by both introgression and artificial selection.…”

Ceramide/Sphingomyelin Rheostat Regulated by Sphingomyelin Synthases and Chronic Diseases in Murine Models

“…In support, a genetic heterozygous mutation of SMS2 ( SGMS2 ) was found in patients with rare skeletal phenotypes and osteoporosis. 144 Patients with a nonsense variant, c148C>T (p.Arg50*) showed childhood onset of osteoporosis, with or without cranial sclerosis. Subjects possessing a missense variant, c.185T>G (p. Ile62Ser) or c.191T>G (p.Met64Arg) presented with more severe symptoms such as neonatal fractures, short stature, and spondylometaphyseal dysplasia.…”

Medical Treatment for Osteoporosis: From Molecular to Clinical Opinions

“…In a recent study, Pekkinen et al evaluated six families with rare skeletal phenotypes and osteoporosis by next-generation sequencing. All families were identified with a heterozygous variant in the sphingomyelin synthase 2 gene (SGMS2), a gene prominently expressed in cortical bones and encoding the plasma membrane-resident SMS2 [20]. Four families shared the same nonsense variant, c.148C>T ( p .Arg50 *), whereas the other families with more severe clinical manifestations had a missense variant, c.185T>G ( p .Ile62Ser) or c.191T>G ( p .Met64Arg).…”

“…Bone biopsies for all showed markedly altered bone material characteristics, including defective bone mineralization. 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 [20].…”