A mutation in the 5′ untranslated region of the human α-galactosidase A gene in high-activity variants inhibits specific protein binding

Recently, normal individuals were identified who had high levels of plasma α-galactosidase A activity and a G to A transition in the 5′ untranslated (5′ UT) region of the α-galactosidase A gene. Electrophoretic mobility shift assays revealed that the wild-type sequence at the site of this mutation complexed with specific nuclear proteins. A standard NF-κB site competed with the 5′ UT site for formation of these DNA-protein complexes. Complex formation was inhibited by the transition mutation. Therefore, the wild-type site might down-modulate expression of the α-galactosidase A gene from this 5′ untranslated region, which includes a previously described protein-binding site for another family of sequence-specific DNA-binding proteins, methylated DNA-binding protein.