Abstract
Loss-of-function mutations of the spermine synthase gene (SMS) result in Snyder-Robinson Syndrome (SRS), a recessive X-linked syndrome characterized by intellectual disability, osteoporosis, hypotonia, speech abnormalities, kyphoscoliosis, and seizures. As SMS catalyzes the biosynthesis of the polyamine spermine from its precursor spermidine, SMS deficiency causes a lack of spermine with an accumulation of spermidine. As polyamines, spermine, and spermidine play essential cellular roles that require tight homeostatic control to ensure normal cell growth, differentiation, and survival. Using patient-derived lymphoblast cell lines, we sought to comprehensively investigate the effects of SMS deficiency on polyamine homeostatic mechanisms including polyamine biosynthetic and catabolic enzymes, derivatives of the natural polyamines, and polyamine transport activity. In addition to decreased spermine and increased spermidine in SRS cells, ornithine decarboxylase activity and its product putrescine were significantly decreased. Treatment of SRS cells with exogenous spermine revealed that polyamine transport was active, as the cells accumulated spermine, decreased their spermidine level, and established a spermidine-to-spermine ratio within the range of wildtype cells. SRS cells also demonstrated elevated levels of tissue transglutaminase, a change associated with certain neurodegenerative diseases. These studies form a basis for further investigations into the leading biochemical changes and properties of SMS-mutant cells that potentially represent therapeutic targets for the treatment of Snyder-Robinson Syndrome.
Highlights
First described in 1969 [1], Snyder-Robinson Syndrome (SRS) is an X-linked intellectual disability syndrome resulting from mutation of the spermine synthase (SMS) gene, located at chromosomeXp22.11 [2]
Custom primers specific for human ODC1, ODC antizyme 1 (OAZ1), AMD1, SRM, SMS, SAT1, histone deacetylase 10 (HDAC10), spermine oxidase (SMOX), PAOX, transglutaminase 2 (TGM2), and GAPDH were synthesized by Integrated
It has been previously reported that spermine concentrations are reduced while spermidine It has been previously reported that spermine concentrations are reduced while spermidine concentrations are increased in SRS lymphoblast cell lines [11,12,13]
Summary
First described in 1969 [1], Snyder-Robinson Syndrome (SRS) is an X-linked intellectual disability syndrome resulting from mutation of the spermine synthase (SMS) gene, located at chromosome. SRS males with the most severe phenotypes lack functional SMS protein, biochemically resulting in elevated levels of intracellular spermidine and near complete depletion of spermine. Spermidine and spermine, along with their precursor putrescine (PUT), constitute the mammalian polyamines, organic polycations that are absolutely essential for growth and proliferation. As their amine groups are protonated at physiological pH, polyamines interact with negatively charged intracellular moieties, including nucleic acids, chromatin, ion channels, certain proteins, and phospholipids [4,5,6,7]. Alterations in intracellular polyamine concentrations can elicit potentially detrimental effects, and polyamine can elicit potentially detrimental effects, and polyamine homeostasis must be tightly regulated through homeostasis must be tightly regulated through biosynthesis, catabolism, uptake, and excretion.
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