HGNC Approved Gene Symbol: SMS
SNOMEDCT: 702416008;
Cytogenetic location: Xp22.11 Genomic coordinates (GRCh38): X:21,940,709-21,994,837 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp22.11 | Intellectual developmental disorder, X-linked syndromic, Snyder-Robinson type | 309583 | X-linked recessive | 3 |
Spermine synthase (EC 2.5.1.22) is 1 of 4 enzymes involved in the synthesis of polyamines from arginine and methionine. The others are ornithine decarboxylase (165640), S-adenosyl-L-methionine decarboxylase (180980), and spermidine synthase (182891).
Korhonen et al. (1995) isolated and sequenced cDNA clones encoding human spermine synthase. The open reading frame encodes a 368-amino acid protein with little sequence similarity to proteins from bacterial and mammalian sources catalyzing almost identical reactions.
Grieff et al. (1997) determined that the SMS gene (which they symbolized SpS) contains 11 exons spanning 54 kb.
Grieff et al. (1997) mapped the SMS gene 38 kb telomeric to the PHEX gene (300550) on Xp22.1.
Crystal Structure
Wu et al. (2008) determined the crystal structure of human SMS, which is a dimer of 2 identical subunits. Each monomer has 3 domains: a C-terminal domain, which contains the active site and is similar in structure to spermidine synthase; a central domain made up of 4 beta-strands; and an N-terminal domain with structural similarity to S-adenosylmethionine decarboxylase (AMD1; 180980), the enzyme that forms the aminopropyl donor substrate. Dimerization occurs mainly through interactions between the N-terminal domains. Deletion of the N-terminal domain led to a complete loss of spermine synthase activity, suggesting that dimerization may be required for activity.
In affected members of a family with Snyder-Robinson X-linked syndromic intellectual developmental disorder (MRXSSR; 309583) originally reported by Snyder and Robinson (1969), Cason et al. (2003) identified a splice site mutation in the SMS gene (300105.0001).
In 2 Mexican brothers with MRXSSR, Becerra-Solano et al. (2009) identified a mutation in the SMS gene (V132G; 300105.0003).
In 2 affected males from a Belgian family with a relatively mild form of Snyder-Robinson syndrome, Zhang et al. (2013) identified a missense mutation in the SMS gene (Y328C; 300105.0004).
In a boy from Italy with Snyder-Robinson syndrome, Peron et al. (2013) identified a missense mutation in the SMS gene (G67E; 300105.0005).
First identified as a mouse model for X-linked hypophosphatemia, the 'Gyro' or 'Gy' mouse (see 300550) also exhibits neurologic abnormalities, including deafness, hyperactivity, circling behavior, and inner ear abnormalities (Lyon et al., 1986). Meyer et al. (1998) found that the Gyro mouse has a partial deletion of both the Sms gene and the Phex gene, making it a contiguous gene syndrome in that species. However, as mutation in the Phex gene alone results in a hypophosphatemic phenotype in the mouse (Hyp) without neurologic manifestations, Meyer et al. (1998) suggested that a deficiency of spermine may explain the additional neurologic findings in the Gy mouse.
In affected members of a family with Snyder-Robinson X-linked syndromic intellectual developmental disorder (MRXSSR; 309583) originally reported by Snyder and Robinson (1969), Cason et al. (2003) identified a G-to-A transition at position +5 of the 5-prime splice site of intron 4 of the SMS gene. The mutation segregated with affected status in the family. Functional studies showed that the mutation reduced the activity of SMS to 5% of controls. Cason et al. (2003) noted that the deficiency of spermine in affected patients suggested a role for polyamines in brain development and cognitive function. The authors suggested cerebellar dysfunction or defective functioning of neurons in the red nucleus.
In affected male members of a Brazilian kindred with Snyder-Robinson X-linked syndromic intellectual developmental disorder (MRXSSR; 309583), de Alencastro et al. (2008) identified a 267G-A transition in exon 2 of the SMS gene, resulting in a gly56-to-ser (G56S) substitution in the N terminus. The phenotype was severe, with profound mental retardation and epilepsy. The G56S mutation segregated with the disease in this family and was not identified in 724 control X chromosomes. Female carriers in the family showed skewed X inactivation. Patient cell lines showed no detectable SMS enzyme activity and an increase in spermadine/spermine ratio.
In 2 Mexican brothers with Snyder-Robinson X-linked syndromic intellectual developmental disorder (MRXSSR; 309583), Becerra-Solano et al. (2009) identified a 496T-G transversion in exon 5 of the SMS gene, resulting in a val132-to-gly (V132G) substitution in a highly conserved residue between the N-terminal domain and the linker domain prior to the C-terminal domain that contains the active site of the enzyme. The mutation was not found in 549 control chromosomes. Spermine protein and activity were significantly decreased in both patients but normal in their unaffected mother. The patients had characteristic features of the disorder, including mental retardation, osteoporosis, multiple fractures, and facial asymmetry.
In 2 affected males from a Belgian family with a relatively mild form of Snyder-Robinson syndrome (MRXSSR; 309583), Zhang et al. (2013) identified a c.1084A-G transition in the SMS gene, resulting in a tyr328-to-cys (Y328C) substitution. The mutation was also present in the unaffected carrier mother. Biochemical studies showed that the mutant protein could form a dimer, but there was significantly decreased SMS activity and a reduction of protein levels to 20% of normal. Transfection of the mutant protein into PC12 neuronal cells showed that the Y328C mutation did not result in significantly decreased neurite length compared to wildtype, and did not cause changes as severe as a loss-of-function mutation (e.g., 300105.0001). However, molecular modeling suggested that the Y328C mutations may increase conformational dynamics of the protein, resulting in destabilization and a loss of catalytic activity.
In a boy with Snyder-Robinson syndrome (MRXSSR; 309583), Peron et al. (2013) identified a c.200G-A transition in exon 3 of the SMS gene, resulting in a gly67-to-glu (G67E) substitution. No spermine synthase activity above baseline was detected in the patient's lymphoblastoid cells. The patient's mother was heterozygous for the mutation and X-inactivation analysis showed mild skewing. In addition to features characteristic of Snyder-Robinson syndrome, the patient also had an ectopic kidney and early-onset epilepsy.
Becerra-Solano, L. E., Butler, J., Castaneda-Cisneros, G., McCloskey, D. E., Wang, X., Pegg, A. E., Schwartz, C. E., Sanchez-Corona, J., Garcia-Ortiz, J. E. A missense mutation, p.V132G, in the X-linked spermine synthase gene (SMS) causes Snyder-Robinson syndrome. Am. J. Med. Genet. 149A: 328-335, 2009. [PubMed: 19206178] [Full Text: https://doi.org/10.1002/ajmg.a.32641]
Cason, A. L., Ikeguchi, Y., Skinner, C., Wood, T. C., Holden, K. R., Lubs, H. A., Martinez, F., Simensen, R. J., Stevenson, R. E., Pegg, A. E., Schwartz, C. E. X-linked spermine synthase gene (SMS) defect: the first polyamine deficiency syndrome. Europ. J. Hum. Genet. 11: 937-944, 2003. [PubMed: 14508504] [Full Text: https://doi.org/10.1038/sj.ejhg.5201072]
de Alencastro, G., McCloskey, D. E., Kliemann, S. E., Maranduba, C. M. C., Pegg, A. E., Wang, X., Bertola, D. A., Schwartz, C. E., Passos-Bueno, M. R., Sertie, A. L. 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. (Letter) J. Med. Genet. 45: 539-543, 2008. [PubMed: 18550699] [Full Text: https://doi.org/10.1136/jmg.2007.056713]
Grieff, M., Whyte, M. P., Thakker, R. V., Mazzarella, R. Sequence analysis of 139 kb in Xp22.1 containing spermine synthase and the 5-prime region of PEX. Genomics 44: 227-231, 1997. [PubMed: 9299240] [Full Text: https://doi.org/10.1006/geno.1997.4876]
Korhonen, V. P., Halmekyto, M., Kauppinen, L., Myohanen, S., Wahlfors, J., Keinanen, T., Hyvonen, T., Alhonen, L., Eloranta, T., Janne, J. Molecular cloning of a cDNA encoding human spermine synthase. DNA Cell Biol. 14: 841-847, 1995. [PubMed: 7546290] [Full Text: https://doi.org/10.1089/dna.1995.14.841]
Lyon, M. F., Scriver, C. R., Baker, L. R. I., Tenenhouse, H. S., Kronick, J., Mandla, S. The Gy mutation: another cause of X-linked hypophosphatemia in mouse. Proc. Nat. Acad. Sci. 83: 4899-4903, 1986. [PubMed: 3460077] [Full Text: https://doi.org/10.1073/pnas.83.13.4899]
Meyer, R. A., Jr., Henley, C. M., Meyer, M. H., Morgan, P. L., McDonald, A. G., Mills, C., Price, D. K. Partial deletion of both the spermine synthase gene and the Pex gene in the X-linked hypophosphatemic, Gyro (Gy) mouse. Genomics 48: 289-295, 1998. [PubMed: 9545633] [Full Text: https://doi.org/10.1006/geno.1997.5169]
Peron, A., Spaccini, L., Norris, J., Bova, S. M., Selicorni, A., Weber, G., Wood, T., Schwartz, C. E., Mastrangelo, M. Snyder-Robinson syndrome: a novel missense mutation in spermine synthase and expansion of the phenotype. Am. J. Med. Genet. 161A: 2316-2320, 2013. Note: Erratum: Am. J. Med. Genet. 164A: 1083 only, 2014. [PubMed: 23897707] [Full Text: https://doi.org/10.1002/ajmg.a.36116]
Snyder, R. D., Robinson, A. Recessive sex-linked mental retardation in the absence of other recognizable abnormalities: report of a family. Clin. Pediat. 8: 669-674, 1969. [PubMed: 5823961] [Full Text: https://doi.org/10.1177/000992286900801114]
Wu, H., Min, J., Zeng, H., McCloskey, D. E., Ikeguchi, Y., Loppnau, P., Michael, A. J., Pegg, A. E., Plotnikov, A. N. Crystal structure of human spermine synthase: implications of substrate binding and catalytic mechanism. J. Biol. Chem. 283: 16135-16146, 2008. [PubMed: 18367445] [Full Text: https://doi.org/10.1074/jbc.M710323200]
Zhang, Z., Norris, J., Kalscheuer, V., Wood, T., Wang, L., Schwartz, C., Alexov, E., Van Esch, H. A Y328C missense mutation in spermine synthase causes a mild form of Snyder-Robinson syndrome. Hum. Molec. Genet. 22: 3789-3797, 2013. [PubMed: 23696453] [Full Text: https://doi.org/10.1093/hmg/ddt229]