The W317X nonsense mutation is predicted to result in a truncated protein of 316 amino acids (35 kD) missing key segments of the active domain (Fig. 3). Full-length HDC, the activity of which depends on the coenzyme pyridoxal 5′-phosphate, is initially produced as a 74-kD product. This is processed to produce multiple isoforms, including a stable isoform of approximately 54 kD, which then forms active homodimers of about 110 kD each.9 Evidence has strongly suggested that the truncating mutation would result in haploinsufficiency9 and lead to decreased histamine in the central nervous system.10 However, given the possibility of incomplete or absent nonsense-mediated decay in the pedigree, and given that the major active form of the HDC enzyme is a homodimer, we speculated that the retained mutant might act through a dominant negative mechanism.
