Supported by an award from NLM, NIH 1R03LM009748
Human DNA sequence differs among individuals and the most common variations are known as single nucleotide polymorphisms, or SNPs. Studies have shown that non-synonymous coding SNPs(nsSNPs - SNPs occurring in protein coding regions which lead to amino acid substitutions) can be responsible for many human diseases. X-linked mental retardation (XLMR) is a particular example of a group of heterogeneous conditions with an estimated frequency of 5-12% in the mentally retarded populations. Specifically, in this regard we focus on the Snyder-Robinson Syndrome caused by defects in spermine synthase (SMS). Polyamines are ubiquitous molecules that interact with variety of other molecules in the cell and are essential for normal cell growth and differentiation. Especially spermine has been shown to modulate ion channel activities is particular cells. We will investigate three missense mutations (G56S, V132G and I150T) within SMS known to cause the Snyder-Robinson Syndrome and will reveal the molecular mechanism of effect of mutations on structure, function and interactions of SMS. Human DNA Recently the 3D structure of the SMS dimer became available and we will take advantage of it. In addition, biochemical experiments combined with site-directed mutagenesis revealed that the dimerization is required for the function of SMS and which are catalytic residues (J Biol Chem , 2008, 283(23):16135-16146). Two of the known missense mutations are located at the dimer interface and perhaps affect the dimerization, while the third one, I150T is in close proximity of the catalytic residues. We will utilize structure-based energy calculations, molecular dynamics simulations, pKa's calculations and sequence analysis to study the effects of these mutations. The goal is to revel the molecular mechanism causing Snyder-Robinson Syndrome and on a long run to suggest a strategy reverting the effect of the missense mutations.
The data files for sMMGB can be download from this link
This project is in collaboration with Professor Charles Schwartz from Greenwood Genetics Center