Compound heterozygous mutations of cytochrome P450 oxidoreductase gene (POR) in two patients with Antley-Bixler syndrome.

Antley-Bixler syndrome (ABS) is characterized by skeletal defects including craniosynostosis and radiohumeral synostosis. Although mutations in the FGFR2 gene have been found in some patients called ABS, genetic heterogeneity of this syndrome has been proposed. We have previously reported three ABS patients with unique abnormalities in steroidogenesis (apparent decreased activity of 17alpha-hydroxylase, 17,20-lyase, and 21-hydroxylase). Decreased activity of lanosterol 14alpha-demethylase has also been described in an ABS patient. Since all these enzymes require cytochrome P450 oxidoreductase (encoded by POR) as an electron donor, we studied POR in two unrelated ABS patients with abnormal steroidogenesis. Direct sequencing of POR revealed that both patients had compound heterozygous mutations (1329insC and R454H in a male patient, 1698insC and R454H in a female patient). The two insertional mutations were assumed to generate truncated and unstable mRNAs. The R454H mutation was assumed to be deleterious because the R454 resides in the FAD-binding domain and is highly conserved among diverse species. Our results demonstrate that mutations in POR cause the ABS phenotype with autosomal recessive inheritance and with characteristic abnormalities in steroidogenesis.