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

Joe Rainger, Hemant Bengani, Leigh Campbell, Eve Anderson, Kishan Sokhi, Wayne Lam, Angelika Riess, Morad Ansari, Sarah Smithson, Melissa Lees, Catherine Mercer, Kathryn McKenzie, Tobias Lengfeld, Blanca Gener Querol, Peter Branney, Stewart McKay, Harris Morrison, Bethan Medina, Morag Robertson, Juergen KohlhaseColin Gordon, Jean Kirk, Dagmar Wieczorek, David R. FitzPatrick

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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.

Original languageEnglish
Pages (from-to)3969-3983
Number of pages15
JournalHuman Molecular Genetics
Issue number18
Publication statusPublished - 15 Sep 2012


  • Pedigree
  • Animals
  • Humans
  • Limb Buds
  • Infant
  • Limb Deformities, Congenital
  • Orotidine-5'-Phosphate Decarboxylase
  • Micrognathism
  • Multienzyme Complexes
  • Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)
  • Genetic Complementation Test
  • Abnormalities, Multiple
  • Orotic Acid
  • Embryo, Mammalian
  • Male
  • Orotate Phosphoribosyltransferase
  • DNA Mutational Analysis
  • Reference Standards
  • Genetic Association Studies
  • Oxidoreductases Acting on CH-CH Group Donors
  • Mice
  • Schizosaccharomyces
  • Mandibulofacial Dysostosis
  • Mutation, Missense
  • Schizosaccharomyces pombe Proteins
  • Child, Preschool
  • Base Sequence
  • Gas Chromatography-Mass Spectrometry
  • Gene Expression Regulation, Developmental
  • Female

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