Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polyamines (putrescine, spermidine, spermine) are ubiquitous, simple molecules that interact with a variety of other molecules in the cell, including nucleic acids, phospholipids and proteins. Various studies indicate that polyamines are essential for normal cell growth and differentiation. Furthermore, these molecules, especially spermine, have been shown to modulate ion channel activities of certain cells. Nonetheless, little is known about the specific cellular functions of these compounds, and extensive laboratory investigations have failed to identify a heritable condition in humans in which polyamine synthesis is perturbed. We report the first polyamine deficiency syndrome caused by a defect in spermine synthase (SMS). The defect results from a splice mutation, and is associated with the Snyder-Robinson syndrome (SRS, OMIM_309583), an X-linked mental retardation disorder. The affected males have mild-to-moderate mental retardation (MR), hypotonia, cerebellar circuitry dysfunction, facial asymmetry, thin habitus, osteoporosis, kyphoscoliosis, decreased activity of SMS, correspondingly low levels of intracellular spermine in lymphocytes and fibroblasts, and elevated spermidine/spermine ratios. The clinical features observed in SRS are consistent with cerebellar dysfunction and a defective functioning of red nucleus neurons, which, at least in rats, contain high levels of spermine. Additionally, the presence of MR reflects a role for spermine in cognitive function, possibly by spermine's ability to function as an 'intrinsic gateway' molecule for inward rectifier K(+) channels.
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PMID:X-linked spermine synthase gene (SMS) defect: the first polyamine deficiency syndrome. 1450 4

Aminopropyltransferases use decarboxylated S-adenosylmethionine as an aminopropyl donor and an amine acceptor to form polyamines. This review covers their structure, mechanism of action, inhibition, regulation and function. The best known aminopropyltransferases are spermidine synthase and spermine synthase but other members of this family including an N(1)-aminopropylagmatine synthase have been characterized. Spermidine synthase is an essential gene in eukaryotes and is very widely distributed. Key regions in the active site, which are very highly conserved, were identified by structural studies with spermidine synthase from Thermotoga maritima bound to S-adenosyl-1,8-diamino-3-thiooctane, a multisubstrate analog inhibitor. A general mechanism for catalysis by aminopropyltransferases can be proposed based on these studies. Spermine synthase is less widely distributed and is not essential for growth in yeast. However, Gy mice lacking spermine synthase have multiple symptoms including a profound growth retardation, sterility, deafness, neurological abnormalities and a propensity to sudden death, which can all be prevented by transgenic expression of spermine synthase. A large reduction in spermine synthase in human males due to a splice site variant causes Snyder-Robinson syndrome with mental retardation, hypotonia and skeletal abnormalities.
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PMID:Aminopropyltransferases: function, structure and genetics. 1642 13

Spermine is present in many organisms including animals, plants, some fungi, some archaea, and some bacteria. It is synthesized by spermine synthase, a highly specific aminopropyltransferase. This review describes spermine synthase structure, genetics, and function. Structural and biochemical studies reveal that human spermine synthase is an obligate dimer. Each monomer contains a C-terminal domain where the active site is located, a central linking domain that also forms the lid of the catalytic domain, and an N-terminal domain that is structurally very similar to S-adenosylmethionine decarboxylase. Gyro mice, which have an X-chromosomal deletion including the spermine synthase (SMS) gene, lack all spermine and have a greatly reduced size, sterility, deafness, neurological abnormalities, and a tendency to sudden death. Mutations in the human SMS lead to a rise in spermidine and reduction of spermine causing Snyder-Robinson syndrome, an X-linked recessive condition characterized by mental retardation, skeletal defects, hypotonia, and movement disorders.
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PMID:Spermine synthase. 1985 64

Polyamines play important roles in cell physiology including effects on the structure of cellular macromolecules, gene expression, protein function, nucleic acid and protein synthesis, regulation of ion channels, and providing protection from oxidative damage. Vertebrates contain two polyamines, spermidine and spermine, as well as their precursor, the diamine putrescine. Although spermidine has an essential and unique role as the precursor of hypusine a post-translational modification of the elongation factor eIF5A, which is necessary for this protein to function in protein synthesis, no unique role for spermine has been identified unequivocally. The existence of a discrete spermine synthase enzyme that converts spermidine to spermine suggest that spermine must be needed and this is confirmed by studies with Gy mice and human patients with Snyder-Robinson syndrome in which spermine synthase is absent or greatly reduced. In both cases, this leads to a severe phenotype with multiple effects among which are intellectual disability, other neurological changes, hypotonia, and reduced growth of muscle and bone. This review describes these alterations and focuses on the roles of spermine which may contribute to these phenotypes including reducing damage due to reactive oxygen species, protection from stress, permitting correct current flow through inwardly rectifying K(+) channels, controlling activity of brain glutamate receptors involved in learning and memory, and affecting growth responses. Additional possibilities include acting as storage reservoir for maintaining appropriate levels of free spermidine and a possible non-catalytic role for spermine synthase protein.
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PMID:The function of spermine. 2439 5

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.
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PMID:Polyamine Homeostasis in Snyder-Robinson Syndrome. 3054 65

Snyder-Robinson syndrome (SRS) is an X-linked syndromic intellectual disability condition caused by variants in the spermine synthase gene (SMS). The syndrome is characterized by facial dysmorphism, thin body build, kyphoscoliosis, osteoporosis, hypotonia, developmental delay and associated neurological features (seizures, unsteady gait, abnormal speech). Until now, only missense variants with a functionally characterized partial loss of function (LoF) have been described. Here we describe the first complete LoF variant, Met303Lysfs*, in a male patient with a severe form of Snyder-Robinson syndrome. He presented with multiple malformations and severly delayed development, and died at 4 months of age. Functional in vitro assays showed a complete absence of functional SMS protein. Taken together, our findings and those of previously reported patients confirm that pathogenic variants of SMS are indeed LoF and that there might exist a genotype-phenotype correlation between the type of variant and the severity of the syndrome.
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PMID:The complete loss of function of the SMS gene results in a severe form of Snyder-Robinson syndrome. 3158 Sep 24