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

Alencastro, Gustavo de; McCloskey, Diane E.; Kliemann, Suzana; Maranduba, C. M. C.; Pegg, Anthony E.; Wang, X; Bertola, Débora Romeo; Schwartz, Charles E.; Passos‐Bueno, Maria Rita; Sertié, Andréa L.

doi:10.1136/jmg.2007.056713

Cited by 64 publications

(94 citation statements)

References 10 publications

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“…To date, only four families with SRS have been described, indicating that the syndrome is either very rare or underdiagnosed. Reevaluation of the original and novel families led to the delineation of a syndromic phenotype additionally characterized by facial dysmorphism, asthenic body build, bone abnormalities including osteoporosis and kyphoscoliosis, nasal dysarthric, coarse, or absent speech, high or cleft palate, urogenital abnormalities, mild short stature and seizures (Arena et al 1996;Cason et al 2003;de Alencastro et al 2008;Becerra-Solano et al 2009;Peron et al 2013).…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

“…The phenotypic aspects of our patients match those of previously published SRS patients. However, some of the typical features including dysarthric speech and movement disorder may only evolve with age and thus hamper a timely diagnosis (de Alencastro et al 2008;Kesler et al 2009;Peron et al 2013). Peron et al recently described a patient with SRS and onset of hypsarrhythmia at the age of 1 year (Peron et al 2013).…”

Section: N 8 -Acetylspermidine As a Novel Potential Biomarker For Snymentioning

confidence: 99%

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N⁸‐acetylspermidine as a potential plasma biomarker for Snyder‐Robinson syndrome identified by clinical metabolomics

Abela

Simmons

Steindl

et al. 2015

J of Inher Metab Disea

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Clinical metabolomics has emerged as a powerful tool to study human metabolism in health and disease. Comparative statistical analysis of untargeted metabolic profiles can reveal perturbations of metabolite levels in diseases and thus has the potential to identify novel biomarkers. Here we have applied a simultaneous genetic-metabolomic approach in twin boys with epileptic encephalopathy of unclear etiology. Clinical exome sequencing identified a novel missense mutation in the spermine synthase gene (SMS) that causes Snyder-Robinson syndrome (SRS). Untargeted plasma metabolome analysis revealed significantly elevated levels of N(8)-acetylspermidine, a precursor derivative of spermine biosynthesis, as a potential novel plasma biomarker for SRS. This result was verified in a third patient with genetically confirmed SRS. This study illustrates the potential of metabolomics as a translational technique to support exome data on a functional and clinical level. Abstract Clinical metabolomics has emerged as a powerful tool to study human metabolism in health and disease. Comparative statistical analysis of untargeted metabolic profiles can reveal perturbations of metabolite levels in diseases and thus has the potential to identify novel biomarkers. Here we have applied a simultaneous genetic-metabolomic approach in twin boys with epileptic encephalopathy of unclear etiology. Clinical exome sequencing identified a novel missense mutation in the spermine synthase gene (SMS) that causes Snyder-Robinson syndrome (SRS). Untargeted plasma metabolome analysis revealed significantly elevated levels of N 8 -acetylspermidine, a precursor derivative of spermine biosynthesis, as a potential novel plasma biomarker for SRS. This result was verified in a third patient with genetically confirmed SRS. This study illustrates the potential of metabolomics as a translational technique to support exome data on a functional and clinical level.

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Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Section: N 8 -Acetylspermidine As a Novel Potential Biomarker For Snymentioning

confidence: 99%

N⁸‐acetylspermidine as a potential plasma biomarker for Snyder‐Robinson syndrome identified by clinical metabolomics

Abela

Simmons

Steindl

et al. 2015

J of Inher Metab Disea

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“…The rare human Snyder-Robinson syndrome is caused by mutations in SpmS located in the X chromosome that drastically reduces the amount of spermine synthase (13,14). This leads to mental retardation, hypotonia, cerebellar circuitry dysfunction, facial asymmetry, thin habitus, osteoporosis, and kyphoscoliosis.…”

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confidence: 99%

Spermine Synthase Deficiency Leads to Deafness and a Profound Sensitivity to α-Difluoromethylornithine*

Wang

Levic

Gratton

et al. 2009

Journal of Biological Chemistry

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Male gyro (Gy) mice, which have an X chromosomal deletion inactivating the SpmS and Phex genes, were found to be profoundly hearing impaired. This defect was due to alteration in polyamine content due to the absence of spermine synthase, the product of the SpmS gene. It was reversed by breeding the Gy strain with CAG/SpmS mice, a transgenic line that ubiquitously expresses spermine synthase under the control of a composite cytomegalovirus-IE enhancer/chicken ␤-actin promoter. There was an almost complete loss of the endocochlear potential in the Gy mice, which parallels the hearing deficiency, and this was also reversed by the production of spermine from the spermine synthase transgene. Gy mice showed a striking toxic response to treatment with the ornithine decarboxylase inhibitor ␣-difluoromethylornithine (DFMO). Within 2-3 days of exposure to DFMO in the drinking water, the Gy mice suffered a catastrophic loss of motor function resulting in death within 5 days. This effect was due to an inability to maintain normal balance and was also prevented by the transgenic expression of spermine synthase. DFMO treatment of control mice or Gy-CAG/SpmS had no effect on balance. The loss of balance in Gy mice treated with DFMO was due to inhibition of polyamine synthesis because it was prevented by administration of putrescine. Our results are consistent with a critical role for polyamines in regulation of Kir channels that maintain the endocochlear potential and emphasize the importance of normal spermidine:spermine ratio in the hearing and balance functions of the inner ear.Polyamines are essential for viability in mammals. Knockouts of the genes for ornithine decarboxylase and S-adenosylmethionine decarboxylase, which are enzymes needed for the synthesis of putrescine, spermidine, and spermine, are lethal at early stages of embryonic development (1, 2). There is convincing evidence that the formation of hypusine in eIF5A, which requires spermidine as a precursor, is essential for eukaryotes (3). However, the function(s) of spermine is not so well established. Yeast mutants with inactivated spermine synthase grow at a normal rate (4). Mammalian cells in culture also grow normally in the presence of inhibitors of spermine synthase (5) or after inactivation of the spermine synthase gene (SpmS) (6 -8

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“…This is, in part, proved by the Snyder-Robinson X-linked mental retardation syndrome [94], characterized by a defect in spermine synthesis, leading to nearly complete loss of the polyamine spermine. We therefore investigated chemical agents selectively destroying the epigenetic shell of eukaryotic euchromatin, found a candidate molecule, and, hence, wish to define it as an 'epigenetic poison'.…”

Section: Discussionmentioning

confidence: 99%

The Spermine Phosphate-Bound Cyclooctaoxygen Sodium Epigenetic Shell of Euchromatin DNA Is Destroyed by the Epigenetic Poison Glyphosate

Kesel¹,

Struys²,

Cellini³

2017

Preprint

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Oxygen exists in two gaseous and six solid allotropic modifications. An additional allotropic modification of oxygen, the cyclooctaoxygen, was predicted to exist in 1990. The first synthesis and characterization of cyclooctaoxygen as its sodium crown complex, isolated in the form of three cytosine nucleoside hydrochloride complexes, was reported in 2016. Cyclooctaoxygen sodium was synthesized from atmospheric oxygen, or catalase effect-generated oxygen, under catalysis of cytosine nucleosides and either ninhydrin or eukaryotic low-molecular weight RNA. The cationic cyclooctaoxygen sodium complex was shown to bind RNA and DNA, to associate with single-stranded DNA and spermine phosphate, and to be essentially non-toxic to cultured mammalian cells at 0.1-1.0 mM concentration. We postulated that cyclooctaoxygen is formed in most eukaryotic cells from dihydrogen peroxide in a catalase reaction catalysed by cytidine and RNA. A molecular biological model was deduced for a first epigenetic shell of eukaryotic euchromatin. This model incorporates an epigenetic explanation for the interactions of the essential micronutrient selenium (as selenite) with eukaryotic euchromatin. The sperminium phosphate/cyclooctaoxygen sodium complex is calculated to cover the actively transcribed regions (2.6%) of bovine lymphocyte interphase genome. Cyclooctaoxygen seems to be naturally absent in hypoxia-induced highly condensed chromatin, taken as a model for eukaryotic metaphase/anaphase/early telophase mitotic chromatin. We hence propose that the cyclooctaoxygen sodium-bridged spermine phosphate and selenite coverage serves as an epigenetic shell of actively transcribed gene regions in eukaryotic 'open' euchromatin DNA. The total herbicide glyphosate (ROUNDUP) and its metabolite (aminomethyl)phosphonic acid (AMPA) are proved to represent 'epigenetic poisons', since they both selectively destroy the cyclooctaoxygen sodium complex. This definition is of reason, since the destruction of cyclooctaoxygen is sufficient to bring the protection shield of human euchromatin into collateral epigenetic collapse.

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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

Cited by 64 publications

References 10 publications

N⁸‐acetylspermidine as a potential plasma biomarker for Snyder‐Robinson syndrome identified by clinical metabolomics

N⁸‐acetylspermidine as a potential plasma biomarker for Snyder‐Robinson syndrome identified by clinical metabolomics

Spermine Synthase Deficiency Leads to Deafness and a Profound Sensitivity to α-Difluoromethylornithine*

The Spermine Phosphate-Bound Cyclooctaoxygen Sodium Epigenetic Shell of Euchromatin DNA Is Destroyed by the Epigenetic Poison Glyphosate

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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

Cited by 64 publications

References 10 publications

N8‐acetylspermidine as a potential plasma biomarker for Snyder‐Robinson syndrome identified by clinical metabolomics

N8‐acetylspermidine as a potential plasma biomarker for Snyder‐Robinson syndrome identified by clinical metabolomics

Spermine Synthase Deficiency Leads to Deafness and a Profound Sensitivity to α-Difluoromethylornithine*

The Spermine Phosphate-Bound Cyclooctaoxygen Sodium Epigenetic Shell of Euchromatin DNA Is Destroyed by the Epigenetic Poison Glyphosate

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Product

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N⁸‐acetylspermidine as a potential plasma biomarker for Snyder‐Robinson syndrome identified by clinical metabolomics

N⁸‐acetylspermidine as a potential plasma biomarker for Snyder‐Robinson syndrome identified by clinical metabolomics