Impaired osteoblast and osteoclast function characterize the osteoporosis of Snyder - Robinson syndrome

Authors

Jessica S. Albert, National Institutes of Health (NIH)
Nisan Bhattacharyya, National Institute of Dental and Craniofacial Research (NIDCR)
Lynne A. Wolfe, National Institutes of Health (NIH)
William P. Bone, National Institutes of Health (NIH)
Valerie Maduro, National Institutes of Health (NIH)
John Accardi, National Institutes of Health (NIH)
David R. Adams, National Institutes of Health (NIH)
Charles E. Schwartz, Greenwood Genetics Center
Joy Norris, National Institute of Dental and Craniofacial Research (NIDCR)
Tim Wood, Greenwood Genetics Center
Rachel I. Gafni, National Institute of Dental and Craniofacial Research (NIDCR)
Michael T. Collins, National Institute of Dental and Craniofacial Research (NIDCR)
Laura L. Tosi, School of Medicine and Health Sciences
Thomas C. Markello, National Institutes of Health (NIH)
William A. Gahl, National Institutes of Health (NIH)
Cornelius F. Boerkoel, National Institutes of Health (NIH)

Document Type

Journal Article

Publication Date

3-7-2015

Journal

Orphanet Journal of Rare Diseases

Volume

10

Issue

1

DOI

10.1186/s13023-015-0235-8

Keywords

Osteoblast; Osteoclast; Osteoporosis; Snyder-Robinson syndrome; Spermine

Abstract

© 2015 Albert et al.; licensee BioMed Central. Background: Snyder-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. Methods: We 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. Results: In 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. Conclusions: Our 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.

APA Citation

Albert, J., Bhattacharyya, N., Wolfe, L., Bone, W., Maduro, V., Accardi, J., Adams, D., Schwartz, C., Norris, J., Wood, T., Gafni, R., Collins, M., Tosi, L., Markello, T., Gahl, W., & Boerkoel, C. (2015). Impaired osteoblast and osteoclast function characterize the osteoporosis of Snyder - Robinson syndrome. Orphanet Journal of Rare Diseases, 10 (1). http://dx.doi.org/10.1186/s13023-015-0235-8