A novel compound heterozygous genotype associated with aromatic amino acid decarboxylase deficiency: Clinical aspects and biochemical studies

Publication date: Available online 10 May 2019Source: Molecular Genetics and MetabolismAuthor(s): Riccardo Montioli, Roberta Battini, Alessandro Paiardini, Manuela Tolve, Mariarita Bertoldi, Carla Carducci, Vincenzo Leuzzi, Carla Borri VoltattorniAbstractAromatic amino acid decarboxylase (AADC) deficiency is a rare autosomal neurometabolic disorder caused by a deficit of AADC, a pyridoxal 5′-phosphate (PLP)-dependent enzyme, which catalyzes the synthesis of dopamine and serotonin. While many studies have highlighted the molecular defects of the homozygous pathogenic variants, so far only a study investigated heterozygous variants at protein level. Here, we report a clinical case of one AADC deficiency compound heterozygous patient bearing the A91V mutation and the novel C410G mutation. To elucidate its enzymatic phenotype, the A91V and C410G homodimers were first expressed in Escherichia coli, purified and characterized. Although both apo variants display an unaltered overall tertiary structure, they show a ̴ 20-fold decreased PLP binding affinity. The C410G mutation only causes a ̴ 4-fold decrease of the catalytic efficiency, while the A91V mutation causes a 1300-fold decrease of the kcat/Km, and changes in the holoAADC consisting in a marked alteration of the tertiary structure and the coenzyme microenvironment. Structural analyses of these mutations are in agreement with these data. Unfortunately, the C410G/A91V heterodimer was constructed, expressed and purified in ra...

Source: Molecular Genetics and Metabolism - May 10, 2019 Category: Genetics & Stem Cells Source Type: research