Abstract
BackgroundSnyder-Robinson Syndrome (SRS) is an X-linked intellectual disability disorder also characterized by osteoporosis, scoliosis, and dysmorphic facial features. It is caused by mutations in SMS, a ubiquitously expressed gene encoding the polyamine biosynthetic enzyme spermine synthase. We hypothesized that the tissue specificity of SRS arises from differential sensitivity to spermidine toxicity or spermine deficiency.MethodsWe performed detailed clinical, endocrine, histopathologic, and morphometric studies on two affected brothers with a spermine synthase loss of function mutation (NM_004595.4:c.443A > G, p.Gln148Arg). We also measured spermine and spermidine levels in cultured human bone marrow stromal cells (hBMSCs) and fibroblasts using the Biochrom 30 polyamine protocol and assessed the osteogenic potential of hBMSCs.ResultsIn addition to the known tissue-specific features of SRS, the propositi manifested retinal pigmentary changes, recurrent episodes of hyper- and hypoglycemia, nephrocalcinosis, renal cysts, and frequent respiratory infections. Bone histopathology and morphometry identified a profound depletion of osteoblasts and osteoclasts, absence of a trabecular meshwork, a low bone volume and a thin cortex. Comparison of cultured fibroblasts from affected and unaffected individuals showed relatively small changes in polyamine content, whereas comparison of cultured osteoblasts identified marked differences in spermidine and spermine content. Osteogenic differentiation of the SRS-derived hBMSCs identified a severe deficiency of calcium phosphate mineralization.ConclusionsOur findings support the hypothesis that cell specific alterations in polyamine metabolism contribute to the tissue specificity of SRS features, and that the low bone density arises from a failure of mineralization.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0235-8) contains supplementary material, which is available to authorized users.
Highlights
Snyder-Robinson Syndrome (SRS) is an X-linked intellectual disability disorder characterized by osteoporosis, scoliosis, and dysmorphic facial features
Exome sequencing identifies a novel spermine synthase (SMS) mutation diagnostic of SRS The propositi had a maternally inherited hemizygous transition (NM_004595.4:c.443A > G) in SMS identified by exome sequencing (Additional file 1: Table S2; full VCF file is available on request) and confirmed by Sanger sequencing (Figure 2A-B)
To better delineate the tissue-specificity of SRS features, we investigated the low bone density of SMS and observed functional osteoblast and osteoclast deficiencies, a marked spermidine and spermine imbalance in human bone marrow stromal cells (hBMSCs) and poor calcium phosphate mineralization by differentiated hBMSCs
Summary
Snyder-Robinson Syndrome (SRS) is an X-linked intellectual disability disorder characterized by osteoporosis, scoliosis, and dysmorphic facial features. It is caused by mutations in SMS, a ubiquitously expressed gene encoding the polyamine biosynthetic enzyme spermine synthase. Homeostasis of the polyamines putrescine, spermidine, and spermine is essential to cell growth and survival [3]. By addition of a propylamine moiety, spermidine synthase (SRM) converts putrescine into spermidine, and spermine synthase (SMS). Mutations of SMS, the gene encoding spermine synthase, cause Snyder-Robinson syndrome (SRS), an X-linked disorder first reported in 1969 [10]. All affected males have hemizygous mutations in SMS that result in reduced SMS activity and a decreased spermine:spermidine ratio.
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