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

• Published in: Human molecular genetics Vol. 21; no. 18; pp. 3969 - 3983
• Main Authors: RAINGER, Joe, BENGANI, Hemant, MERCER, Catherine, MCKENZIE, Kathryn, LENGFELD, Tobias, QUEROKL, Blanca Gener, BRANNEY, Peter, MCKAY, Stewart, MORRISON, Harris, MEDINA, Bethan, ROBERTSON, Morag, KOHLHASE, Jurgen, CAMPBELL, Leigh, GORDON, Colin, KIRK, Jean, WIECZOREK, Dagmar, FITZPATRICK, David R, ANDERSON, Eve, SOKHI, Kishan, LAM, Wayne, RIESS, Angelika, ANSARI, Morad, SMITHSON, Sarah, LEES, Melissa
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.09.2012
• Subjects: Abnormalities, Multiple - enzymology; Abnormalities, Multiple - genetics; Abnormalities, Multiple - urine; Animals; Base Sequence; Biological and medical sciences; Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) - genetics; Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) - metabolism; Child, Preschool; Complementation; Complex syndromes; DNA Mutational Analysis; Embryo, Mammalian - metabolism; Embryo, Mammalian - pathology; Female; Fundamental and applied biological sciences. Psychology; Gas Chromatography-Mass Spectrometry - standards; Gene Expression Regulation, Developmental; Genetic Association Studies; Genetic Complementation Test; Genetics of eukaryotes. Biological and molecular evolution; Humans; Infant; Limb Buds - metabolism; Limb Buds - pathology; Limb Deformities, Congenital - enzymology; Limb Deformities, Congenital - genetics; Limb Deformities, Congenital - urine; Male; Mandibulofacial Dysostosis - enzymology; Mandibulofacial Dysostosis - genetics; Mandibulofacial Dysostosis - urine; Medical genetics; Medical sciences; Mice; Micrognathism - enzymology; Micrognathism - genetics; Micrognathism - urine; Molecular and cellular biology; Multienzyme Complexes - genetics; Multienzyme Complexes - metabolism; Mutation, Missense; Orotate Phosphoribosyltransferase - genetics; Orotate Phosphoribosyltransferase - metabolism; Orotic Acid - analogs & derivatives; Orotic Acid - urine; Orotidine-5'-Phosphate Decarboxylase - genetics; Orotidine-5'-Phosphate Decarboxylase - metabolism; Oxidoreductases Acting on CH-CH Group Donors - deficiency; Oxidoreductases Acting on CH-CH Group Donors - genetics; Oxidoreductases Acting on CH-CH Group Donors - metabolism; Pedigree; Reference Standards; Schizosaccharomyces - genetics; Schizosaccharomyces - growth & development; Schizosaccharomyces pombe Proteins - genetics; Partial; Deficiency; Diseases of the osteoarticular system; Dysostosis; Genetics; Subgroup; Syndrome
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/dds218

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.