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Biallelic mutations in the gene encoding DHOdehase [dihydroorotate dehydrogenase ( DHODH )], an enzyme required for  de novo  pyrimidine biosynthesis, have been identified as the cause of Miller (Genée–Weidemann or postaxial acrofacial dysostosis) syndrome (MIM 263750). We report compound heterozygous  DHODH  mutations in four additional families with typical Miller syndrome. Complementation in auxotrophic yeast demonstrated reduced pyrimidine synthesis and  in vitro  enzymatic analysis confirmed reduced DHOdehase activity in 11 disease-associated missense mutations, with 7 alleles showing discrepant activity between the assays. These discrepancies are partly explained by the domain structure of DHODH and suggest both assays are useful for interpretation of individual alleles. However, in all affected individuals, the genotype predicts that there should be significant residual DHOdehase activity. Urine samples obtained from two mutation-positive cases showed elevated levels of orotic acid (OA) but not dihydroorotate (DHO), an unexpected finding since these represent the product and the substrate of DHODH enzymatic activity, respectively. Screening of four unrelated cases with overlapping but atypical clinical features showed no mutations in either  DHODH  or the other  de novo  pyrimidine biosynthesis genes ( CAD ,  UMPS ), with these cases also showing normal levels of urinary OA and DHO.  In situ  analysis of mouse embryos showed  Dhodh ,  Cad  and  Umps  to be strongly expressed in the pharyngeal arch and limb bud, supporting a site- and stage-specific requirement for  de novo  pyrimidine synthesis. The developmental sensitivity to reduced pyrimidine synthesis capacity may reflect the requirement for an exceptional mitogenic response to growth factor signalling in the affected tissues.

human molecular genetics

Miller (Genée–Wiedemann) syndrome represents a clinically and biochemically distinct subgroup of postaxial acrofacial dysostosis associated with partial deficiency of DHODH