The mechanism by which mutations in DHODH cause Miller syndrome is unclear. The primary known function of dihydroorotate dehydrogenase is to catalyze the conversion of dihydroorotate to orotic acid, an intermediate in the pyrimidine de novo biosynthesis pathway (Supplementary Figure 3)20. Orotic acid is subsequently converted to uridine monophosphate (UMP) by UMP synthase. Pyrimidine biosynthesis might be particularly sensitive to the step mediated by dihydroorotate dehydrogenase21 and the classical rudimentary phenotype in D. melanogaster, reported by T.H. Morgan in 1910 and characterized by wing anomalies, defective oogenesis, and malformed posterior legs, is caused by mutations in the same pathway22-24. However, the clinical characteristics of the other inborn errors of pyrimidine biosynthesis such as orotic aciduria, caused by mutations in UMP synthase, do not include malformations. Indeed, inborn errors of metabolism are, in general, a rare cause of birth defects so DHODH would be given little weight a priori as a candidate for a multiple malformation disorder. Thus, the discovery that mutations in DHODH cause Miller syndrome reveals both a new role for pyrimidine metabolism in craniofacial and limb development as well as a novel function of dihydroorotate dehydrogenase that remains to be explored.
