Pyridoxine non-responsive p.R336C mutation alters the molecular properties of cystathionine beta-synthase leading to severe homocystinuria phenotype

<ul><li>The prevalence of homocystinuria in Qatar is 1:1800, mainly due to a founder missense mutation p.R336C.</li><li>The cystathionine beta-synthase (CBS) R336C mutant was bacterially expressed, purified and its molecular properties were compared to CBS wild type (WT) recombinant protein.</li><li>Our data revealed that p.R336C mutation results in a dramatic reduction (∼86%) of CBS enzymatic activity.</li><li>Circular Dichroism experiments suggested that the p.R336C mutation does not significantly alter the secondary structure of the CBS protein.</li><li>CD spectra also revealed distinct differences in the thermal unfolding mechanisms of CBS WT and R336C mutant protein species.</li><li>Chemical denaturation experiments indicated that the WT CBS protein is thermodynamically more stable than the R336C mutant, suggesting a destabilizing effect of the p.R336C mutation.</li><li>This study provides mechanistic insight into the pathogenicity of the p.R336C mutation that leads to a severe homocystinuria phenotype.</li></ul><h2>Other Information</h2><p dir="ltr">Published in: Biochimica et Biophysica Acta (BBA) - General Subjects<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.bbagen.2022.130148" target="_blank">https://dx.doi.org/10.1016/j.bbagen.2022.130148</a></p><p dir="ltr">Additional institutions affiliated with: Hamad Medical Corporation, Hamad General Hospital - HMC, Women's Wellness and Research Center - HMC, Interim Translational Research Institute - HMC</p>