title: Impaired osteoblast and osteoclast function characterize the osteoporosis of Snyder - Robinson syndrome.
abstract: 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.
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20814, USA. albertjs@mail.nih.gov.|Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA. albertjs@mail.nih.gov.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Albert
authors.affiliation: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Disease Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA. bhattacharyyan@nidcr.nih.gov.
authors.forename: Nisan
authors.initials: N
authors.lastname: Bhattacharyya
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20814, USA. wolfela@mail.nih.gov.|Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA. wolfela@mail.nih.gov.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Wolfe
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20814, USA. william.bone@nih.gov.
authors.forename: William P
authors.initials: WP
authors.lastname: Bone
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20814, USA. vbraden@mail.nih.gov.
authors.forename: Valerie
authors.initials: V
authors.lastname: Maduro
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20814, USA. ja434650@gmail.com.
authors.forename: John
authors.initials: J
authors.lastname: Accardi
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20814, USA. dadams1@mail.nih.gov.|Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA. dadams1@mail.nih.gov.
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
authors.affiliation: J.C. Self Research Institute, Greenwood Genetics Centre, Greenwood, SC, 29646, USA. ceschwartz@ggc.org.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.affiliation: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Disease Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA. jwnorris@ggc.org.
authors.forename: Joy
authors.initials: J
authors.lastname: Norris
authors.affiliation: J.C. Self Research Institute, Greenwood Genetics Centre, Greenwood, SC, 29646, USA. tim@ggc.org.
authors.forename: Tim
authors.initials: T
authors.lastname: Wood
authors.affiliation: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Disease Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA. gafnir@mail.nih.gov.
authors.forename: Rachel I
authors.initials: RI
authors.lastname: Gafni
authors.affiliation: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Disease Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA. mc247k@nih.gov.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Collins
authors.affiliation: George Washington University School of Medicine, Washington, DC, USA. LTOSI@childrensnational.org.|Children's National Medical Center, Washington, DC, USA. LTOSI@childrensnational.org.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Tosi
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20814, USA. markellot@mail.nih.gov.|Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA. markellot@mail.nih.gov.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Markello
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20814, USA. gahlw@helix.nih.gov.|Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA. gahlw@helix.nih.gov.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, 20814, USA. cboerkoel@gmail.com.
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Boerkoel
mesh_terms: D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000378:metabolism / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology*; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology*; D010024:Osteoporosis / Q000378:metabolism / Q000473:pathology*; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D013097:Spermine Synthase / Q000235:genetics / Q000378:metabolism
chemical_list: D013096:Spermine; D013097:Spermine Synthase; D013095:Spermidine