Human molecular genetics

A comprehensive picture of the mutations associated with aromatic amino acid decarboxylase deficiency: from molecular mechanisms to therapy implications.

PMID 24865461


Dopa decarboxylase (DDC), or aromatic amino acid decarboxylase (AADC), is a pyridoxal 5'-phosphate enzyme responsible for the production of the neurotransmitters dopamine and serotonin. Deficit of this enzyme causes AADC deficiency, an inherited neurometabolic disorder. To date, 18 missense homozygous mutations have been identified through genetic screening in ∼80 patients. However, little is known about the mechanism(s) by which mutations cause disease. Here we investigated the impact of these pathogenic mutations and of an artificial one on the conformation and the activity of wild-type DDC by a combined approach of bioinformatic, spectroscopic and kinetic analyses. All mutations reduce the kcat value, and, except the mutation R347Q, alter the tertiary structure, as revealed by an increased hydrophobic surface and a decreased near-UV circular dichroism signal. The integrated analysis of the structural and functional consequences of each mutation strongly suggests that the reason underlying the pathogenicity of the majority of disease-causing mutations is the incorrect apo-holo conversion. In fact, the most remarkable effects are seen upon mutation of residues His70, His72, Tyr79, Phe80, Pro81, Arg462 and Arg447 mapping to or directly interacting with loop1, a structural key element involved in the apo-holo switch. Instead, different mechanisms are responsible for the pathogenicity of R347Q, a mere catalytic mutation, and of L38P and A110Q mutations causing structural-functional defects. These are due to local perturbation transmitted to the active site, as predicted by molecular dynamic analyses. Overall, the results not only give comprehensive molecular insights into AADC deficiency, but also provide an experimental framework to suggest appropriate therapeutic treatments.