Abstract
Heterozygous mutations in the gene encoding the sphingomyelin synthase 2, SGMS2, have recently been linked to childhood-onset osteoporosis and skeletal dysplasia. One nonsense variant at position c.148C>T (p.Arg50*) has been associated with mild bone fragility with or without cranial sclerosis. Here we assessed the effect of the SGMS2 p.Arg50* variant in two unrelated probands with childhood-onset osteoporosis and their unaffected family members. We found that the p.Arg50* variant was associated with phenotypic variability, ranging from absence of a bone phenotype to severe vertebral compression fractures and low lumbar spine areal bone mineral density (BMD) as measured by dual energy x-ray absorptiometry. Peripheral quantitative computed tomography of the radius and tibia in the two probands revealed low cortical volumetric BMD and reduced cortical thickness. In addition, both probands were obese and suffered from muscle function deficits compared to sex- and age-matched controls. Long-term bisphosphonate treatment was associated with reshaping of previously compressed vertebral bodies.
Highlights
Monogenic bone fragility disorders are caused by genetic variants that can be inherited in an autosomal dominant, autosomal recessive or X-linked fashion. [1] The most common cause of monogenic bone fragility disorders are pathogenic variants affecting the genes encoding collagen type I (COL1A1 and COL1A2). [2] Recently, heterozygous mutations in SGMS2, the gene encoding sphingomyelin synthase 2 (SMS2), have been linked to childhood-onset osteoporosis and skeletal dysplasia. [3] Sphingomyelin is one of the major lipids forming the plasma membrane
In this study, we found that individuals with the p.Arg50* variant in SGMS2 seem to present with phenotypic variability, ranging from absence of a bone phenotype to severe vertebral compression fractures and low bone mineral density (BMD) resembling OI
Intravenous bisphosphonate treatment was associated with a significant increase in BMD at the lumbar spine and distal radius as well as reshaping of previously compressed vertebral bodies
Summary
Monogenic bone fragility disorders are caused by genetic variants that can be inherited in an autosomal dominant, autosomal recessive or X-linked fashion. [1] The most common cause of monogenic bone fragility disorders are pathogenic variants affecting the genes encoding collagen type I (COL1A1 and COL1A2). [2] Recently, heterozygous mutations in SGMS2, the gene encoding sphingomyelin synthase 2 (SMS2), have been linked to childhood-onset osteoporosis and skeletal dysplasia. [3] Sphingomyelin is one of the major lipids forming the plasma membrane. [9] In humans, the available evidence suggests that some heterozygous missense variants in SGMS2 (NM_001136257) have a dominant negative effect and lead to severe bone fragility and spondylometaphyseal dysplasia, while one recurrent nonsense variant (c.148C>T, p.Arg50*) has been associated with milder bone fragility with or without cranial sclerosis. The mechanism by which the heterozygous SGMS2 p.Arg50* variant leads to bone fragility is unclear. [10] Regarding medical treatment of bone fragility related to the SGMS2 p.Arg50* variant, it has been noted that bisphosphonate treatment was associated with decreased peripheral fracture rates in some patients, [3] but the effect of long-term intravenous bisphosphonate therapy on vertebral shape has not been investigated Even though SGMS2 is most highly expressed in cortical bone, SGMS2 expression is found in muscle. [3] SMS2 deficiency could lead to accumulation of its substrate ceramide, which could alter muscle function since ceramide inhibits insulin-stimulated glucose entry into rat myocytes. [10] Regarding medical treatment of bone fragility related to the SGMS2 p.Arg50* variant, it has been noted that bisphosphonate treatment was associated with decreased peripheral fracture rates in some patients, [3] but the effect of long-term intravenous bisphosphonate therapy on vertebral shape has not been investigated
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