{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSMS, a pivotal enzyme in polyamine metabolism, is essential for normal neurodevelopment and cellular homeostasis. Loss‐of‐function mutations in the SMS gene are causative for Snyder–Robinson syndrome, an X‐linked disorder characterized by intellectual disability, epilepsy, and distinctive skeletal features. Neuroimaging studies further reveal that individuals with compromised SMS function exhibit altered brain volumes in regions critical for cognition and motor control."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, SMS catalyzes the conversion of spermidine to spermine—a reaction fundamental to maintaining the appropriate balance of polyamines for cell proliferation, differentiation, and apoptosis. Detailed biochemical and structural analyses have shown that SMS is highly intolerant to amino acid changes; pathogenic missense mutations (for example, p.G56S and others) lead to significant enzyme destabilization, impaired homodimer formation, and consequent loss of catalytic activity. These findings underscore the evolutionary precision of SMS and explain the severe phenotypes associated with its deficiency."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its developmental roles, SMS dysregulation also participates in oncogenic processes. In colorectal cancer, SMS is frequently overexpressed, and its aberrant activity shifts the spermidine/spermine ratio, leading to downstream effects such as inhibition of FOXO3a acetylation. This in turn facilitates FOXO3a nuclear translocation and the upregulation of proapoptotic factors like Bim, a pathway that delineates a key survival signal in tumor cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, SMS function is integral to skeletal homeostasis. In vitro studies using human mesenchymal stem cells have demonstrated that changes in SMS activity—and the consequent alterations in the spermidine to spermine ratio—significantly influence osteoblast differentiation and matrix mineralization. Such findings provide insights into how SMS deficiency contributes to the skeletal defects observed in Snyder–Robinson syndrome and may open avenues for therapeutic modulation in bone-related pathologies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "G de Alencastro, D E McCloskey, S E Kliemann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "New SMS mutation leads to a striking reduction in spermine synthase protein function and a severe form of Snyder-Robinson X-linked recessive mental retardation syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmg.2007.056713"}], "href": "https://doi.org/10.1136/jmg.2007.056713"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18550699"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18550699"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "L E Becerra-Solano, J Butler, G Castañeda-Cisneros, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A missense mutation, p.V132G, in the X-linked spermine synthase gene (SMS) causes Snyder-Robinson syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.32641"}], "href": "https://doi.org/10.1002/ajmg.a.32641"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19206178"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19206178"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Shelli R Kesler, Charles Schwartz, Roger E Stevenson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The impact of spermine synthase (SMS) mutations on brain morphology."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurogenetics (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10048-009-0184-2"}], "href": "https://doi.org/10.1007/s10048-009-0184-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19277733"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19277733"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xianzun Tao, Jiaqi Liu, Zoraida Diaz-Perez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reduction of spermine synthase enhances autophagy to suppress Tau accumulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-024-06720-8"}], "href": "https://doi.org/10.1038/s41419-024-06720-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38740758"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38740758"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Charles E Schwartz, Xaiojing Wang, Roger E Stevenson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Spermine synthase deficiency resulting in X-linked intellectual disability (Snyder-Robinson syndrome)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Methods Mol Biol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/978-1-61779-034-8_28"}], "href": "https://doi.org/10.1007/978-1-61779-034-8_28"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21318891"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21318891"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Zhe Zhang, Joy Norris, Charles Schwartz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "In silico and in vitro investigations of the mutability of disease-causing missense mutation sites in spermine synthase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0020373"}], "href": "https://doi.org/10.1371/journal.pone.0020373"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21647366"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21647366"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Zhe Zhang, Yueli Zheng, Margo Petukh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Enhancing human spermine synthase activity by engineered mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Comput Biol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pcbi.1002924"}], "href": "https://doi.org/10.1371/journal.pcbi.1002924"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23468611"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23468611"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Yunhui Peng, Joy Norris, Charles Schwartz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Revealing the Effects of Missense Mutations Causing Snyder-Robinson Syndrome on the Stability and Dimerization of Spermine Synthase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms17010077"}], "href": "https://doi.org/10.3390/ijms17010077"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26761001"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26761001"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Yubin Guo, Qing Ye, Pan Deng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-020-17067-x"}], "href": "https://doi.org/10.1038/s41467-020-17067-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32591507"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32591507"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Amin Cressman, David Morales, Zhenyang Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effects of Spermine Synthase Deficiency in Mesenchymal Stromal Cells Are Rescued by Upstream Inhibition of Ornithine Decarboxylase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms25052463"}], "href": "https://doi.org/10.3390/ijms25052463"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38473716"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38473716"}]}]}]}