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.
Highlights
Osteoporosis is a major clinical and public health concern with significant morbidity, disability, and mortality [1] The underlying causes remain incompletely understood
We identified a heterozygous variant in sphingomyelin synthase 2 gene (SGMS2), a gene prominently expressed in cortical bone and encoding the plasma membrane–resident sphingomyelin synthase SMS2
The recruitment occurred by two means: (a) by asking clinicians about phenotypically matching patients with the combination of osteoporosis or fractures and sclerotic cranial lesions, similar to that described in calvarial doughnut lesions (CDLs), and, (b) after identification of the gene defect, by genetic and phenotypic match through GeneMatcher [4]
Summary
Osteoporosis is a major clinical and public health concern with significant morbidity, disability, and mortality [1] The underlying causes remain incompletely understood. Rare inherited skeletal disorders have often shed light on the genetic and molecular mechanisms governing bone health [2]. Several such rare disorders are associated with early-onset osteoporosis, with or without additional clinical traits. One example is osteoporosis with calvarial doughnut lesions (CDLs) (Online Mendelian Inheritance in Man [OMIM] #126550). This autosomal dominant skeletal disorder is characterized by low-bone mineral density, increased spinal and peripheral fractures, and sclerotic, doughnut-shaped lesions in the cranial bones.
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