Mutations in a Delta(8)-Delta(7) sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata

Tattered (Td) is an X-linked, semi-dominant mouse mutation associated with prenatal male lethality(1). Heterozygous females are small and at 4-5 days of age develop patches of hyperkeratotic skin where no hair grows, resultin g in a striping of the coat in adults(2). Craniofacial anomalies and twiste d toes have also been observed in some affected females(3,4). A potential s econd allele of Td has also been described(5). The phenotype of Td is simil ar to that seen in heterozygous females with human X-linked dominant chondr odysplasia punctata (CDPX2, alternatively known as X-linked dominant Conrad i-Hunermann-Happle syndrome) as well as another X-linked, semi-dominant mou se mutation, bare patches (Bpa). The Bpa gene has recently been identified( 6) and encodes a protein with homology to 3 beta-hydroxysteroid dehydrogena ses that functions in one of the later steps of cholesterol biosynthesis. C DPX2 patients display skin defects including linear or whorled atrophic and pigmentary lesions, striated hyperkeratosis, coarse lusterless hair and al opecia, cataracts and skeletal abnormalities including short stature, rhizo melic shortening of the limbs, epiphyseal stippling and craniofacial defect s (MIM 302960). We have now identified the defect in Td mice as a single am ino acid substitution in the Delta(8)-Delta(7) sterol isomerase emopamil bi nding protein (Ebp; encoded by Ebp in mouse) and identified alterations in human EBP in seven unrelated CDPX2 patients.