Computational analysis of missense mutations causing Snyder‐Robinson syndrome

The Snyder‐Robinson syndrome is caused by missense mutations in the spermine sythase gene that encodes a protein (SMS) of 529 amino acids. Here we investigate, in silico, the molecular effect of three missense mutations, c.267G>A (p.G56S), c.496T>G (p.V132G), and c.550T>C (p.I150T) in SMS that were clinically identified to cause the disease. Single‐point energy calculations, molecular dynamics simulations, and pKa calculations revealed the effects of these mutations on SMS's stability, flexibility, and interactions. It was predicted that the catalytic residue, Asp276, should be protonated prior binding the substrates. The pKa calculations indicated the p.I150T mutation causes pKa changes with respect to the wild‐type SMS, which involve titratable residues interacting with the S‐methyl‐5′‐thioadenosine (MTA) substrate. The p.I150T missense mutation was also found to decrease the stability of the C‐terminal domain and to induce structural changes in the vicinity of the MTA binding site. The other two missense mutations, p.G56S and p.V132G, are away from active site and do not perturb its wild‐type properties, but affect the stability of both the monomers and the dimer. Specifically, the p.G56S mutation is predicted to greatly reduce the affinity of monomers to form a dimer, and therefore should have a dramatic effect on SMS function because dimerization is essential for SMS activity. Hum Mutat 31:1043–1049, 2010. © 2010 Wiley‐Liss, Inc.

[1]  T. A. Jones,et al.  Databases in protein crystallography. , 1998, Acta crystallographica. Section D, Biological crystallography.

[2]  Benzhuo Lu,et al.  An Adaptive Fast Multipole Boundary Element Method for Poisson−Boltzmann Electrostatics , 2009, Journal of chemical theory and computation.

[3]  L. Marton,et al.  Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases , 2007, Nature Reviews Drug Discovery.

[4]  David Haussler,et al.  LS-SNP: large-scale annotation of coding non-synonymous SNPs based on multiple information sources , 2005, Bioinform..

[5]  Jianpeng Ma,et al.  CHARMM: The biomolecular simulation program , 2009, J. Comput. Chem..

[6]  M. Brandi,et al.  Characterization of a Non‐UBA Domain Missense Mutation of Sequestosome 1 (SQSTM1) in Paget's Disease of Bone , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[7]  A. Pegg,et al.  Spermine synthase , 2009, Cellular and Molecular Life Sciences.

[8]  A. Robinson,et al.  Recessive Sex-Linked Mental Retardation in the Absence of Other Recognizable Abnormalities , 1969, Clinical pediatrics.

[9]  Emil Alexov,et al.  Modeling effects of human single nucleotide polymorphisms on protein-protein interactions. , 2009, Biophysical journal.

[10]  E. Gerner,et al.  Polyamines and cancer: old molecules, new understanding , 2004, Nature Reviews Cancer.

[11]  Piero Fariselli,et al.  I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure , 2005, Nucleic Acids Res..

[12]  Andrej Sali,et al.  Improving Functional Annotation of Non-Synonomous SNPs with Information Theory , 2005, Pacific Symposium on Biocomputing.

[13]  Anand K. Srivastava,et al.  Biological Features for Sequence-Based Prediction of Protein Stability Changes upon Amino Acid Substitutions , 2009, 2009 International Joint Conference on Bioinformatics, Systems Biology and Intelligent Computing.

[14]  M. I. Galindo,et al.  Missense mutations in the SH3TC2 protein causing Charcot-Marie-Tooth disease type 4C affect its localization in the plasma membrane and endocytic pathway. , 2009, Human molecular genetics.

[15]  Joost Schymkowitz,et al.  Bioinformatics Applications Note Snpeffect V2.0: a New Step in Investigating the Molecular Phenotypic Effects of Human Non-synonymous Snps , 2022 .

[16]  W. C. Still,et al.  Semianalytical treatment of solvation for molecular mechanics and dynamics , 1990 .

[17]  A. Pegg,et al.  Effect of spermine synthase deficiency on polyamine biosynthesis and content in mice and embryonic fibroblasts, and the sensitivity of fibroblasts to 1,3-bis-(2-chloroethyl)-N-nitrosourea. , 2000, The Biochemical journal.

[18]  Liangjiang Wang,et al.  Sequence feature-based prediction of protein stability changes upon amino acid substitutions , 2010, BMC Genomics.

[19]  E. Gerner,et al.  APC-dependent changes in expression of genes influencing polyamine metabolism, and consequences for gastrointestinal carcinogenesis, in the Min mouse. , 1999, Carcinogenesis.

[20]  C. Skinner,et al.  X-linked spermine synthase gene (SMS) defect: the first polyamine deficiency syndrome , 2003, European Journal of Human Genetics.

[21]  J. Śanchez-Corona,et al.  A missense mutation, p.V132G, in the X‐linked spermine synthase gene (SMS) causes Snyder–Robinson syndrome , 2009, American journal of medical genetics. Part A.

[22]  Emil Alexov,et al.  On the electrostatic component of protein-protein binding free energy , 2008, PMC biophysics.

[23]  M. Bewley,et al.  Aminopropyltransferases: function, structure and genetics. , 2006, Journal of biochemistry.

[24]  Emil Alexov,et al.  Role of the protein side‐chain fluctuations on the strength of pair‐wise electrostatic interactions: Comparing experimental with computed pKas , 2002, Proteins.

[25]  Thomas C. Bruice,et al.  Comparison of the Dynamics for Ground-State and Transition-State Structures in the Active Site of Catechol O-Methyltransferase , 2000 .

[26]  Matthieu Schapira,et al.  A survey of proteins encoded by non-synonymous single nucleotide polymorphisms reveals a significant fraction with altered stability and activity. , 2009, The Biochemical journal.

[27]  W. L. Jorgensen,et al.  The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin. , 1988, Journal of the American Chemical Society.

[28]  Richard C Trembath,et al.  A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups. , 2004, Human molecular genetics.

[29]  C. Beetz,et al.  Isoform‐specific increase of spastin stability by N‐terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia , 2007, European journal of neurology.

[30]  G. Merino,et al.  Natural Allelic Variants of Bovine ATP-Binding Cassette Transporter ABCG2: Increased Activity of the Ser581 Variant and Development of Tools for the Discovery of New ABCG2 Inhibitors , 2009, Drug Metabolism and Disposition.

[31]  M. Michael Gromiha,et al.  CUPSAT: prediction of protein stability upon point mutations , 2006, Nucleic Acids Res..

[32]  E. Alexov,et al.  Combining conformational flexibility and continuum electrostatics for calculating pK(a)s in proteins. , 2002, Biophysical journal.

[33]  Z. Xiang,et al.  Extending the accuracy limits of prediction for side-chain conformations. , 2001, Journal of molecular biology.

[34]  Emil Alexov,et al.  Structural and functional consequences of single amino acid substitutions in the pyrimidine base binding pocket of Escherichia coli CMP kinase , 2007, The FEBS journal.

[35]  Shuangye Yin,et al.  Eris: an automated estimator of protein stability , 2007, Nature Methods.

[36]  Peng Yue,et al.  SNPs3D: Candidate gene and SNP selection for association studies , 2006, BMC Bioinformatics.

[37]  E. Alexov,et al.  Approaches and resources for prediction of the effects of non-synonymous single nucleotide polymorphism on protein function and interactions. , 2008, Current pharmaceutical biotechnology.

[38]  Alberto Riva,et al.  SNPper: retrieval and analysis of human SNPs , 2002, Bioinform..

[39]  Gerard J Kleywegt,et al.  Pound-wise but penny-foolish: How well do micromolecules fare in macromolecular refinement? , 2003, Structure.

[40]  Gerard J. Kleywegt,et al.  Crystallographic refinement of ligand complexes , 2006, Acta crystallographica. Section D, Biological crystallography.

[41]  Richard J. B. Dobson,et al.  Predicting deleterious nsSNPs: an analysis of sequence and structural attributes , 2006, BMC Bioinformatics.

[42]  Jan H. Jensen,et al.  Very fast prediction and rationalization of pKa values for protein–ligand complexes , 2008, Proteins.

[43]  E. Alexov,et al.  Incorporating protein conformational flexibility into the calculation of pH-dependent protein properties. , 1997, Biophysical journal.

[44]  Holger Gohlke,et al.  The Amber biomolecular simulation programs , 2005, J. Comput. Chem..

[45]  François Stricher,et al.  The FoldX web server: an online force field , 2005, Nucleic Acids Res..

[46]  C. Schwartz,et al.  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 , 2008, Journal of Medical Genetics.

[47]  Philip E. Bourne,et al.  The RCSB PDB information portal for structural genomics , 2005, Nucleic Acids Res..