Certain mutations in the ALDH7A1 gene cause pyridoxine-dependent epilepsy (PDE), an autosomal recessive metabolic disease characterized by seizures, and in some cases, intellectual disability. The mutational spectrum of PDE is vast and includes over 70 missense mutations. This review summarizes the current state of biochemical and biophysical research on the impact of PDE missense mutations on the structure and catalytic activity ALDH7A1. Paradoxically, some mutations that target active site residues have a relatively modest impact on structure and function, while those remote from the active site can have profound effects. For example, missense mutations targeting remote residues in oligomer interfaces tend to strongly impact catalytic function by inhibiting formation of the active tetramer. These results shows that it remains very difficult to predict the impact of missense mutations, even when the structure of the wild-type enzyme is known. Additional biophysical analyses of many more disease-causing mutations are needed to develop the rules for predicting the impact of genetic mutations on enzyme structure and catalytic function.

ALDH7A1中的某些突变基因导致吡哆醇依赖性癫痫（PDE），这是一种常染色体隐性遗传代谢疾病，其特征是癫痫发作，在某些情况下，智力残疾。PDE 的突变谱很广，包括 70 多个错义突变。本综述总结了PDE错义突变对ALDH7A1结构和催化活性影响的生化和生物物理研究现状。矛盾的是，一些针对活性位点残基的突变对结构和功能的影响相对较小，而那些远离活性位点的突变可能会产生深远的影响。例如，针对寡聚体界面中远程残基的错义突变往往会通过抑制活性四聚体的形成来强烈影响催化功能。这些结果表明，即使野生型酶的结构已知，也很难预测错义突变的影响。需要对更多致病突变进行额外的生物物理分析，以制定预测基因突变对酶结构和催化功能影响的规则。