Novel and recurrent EBP mutations in X-linked dominant chondrodysplasia punctata

Chondrodysplasia punctata (CDP) is a heterogeneous group of skeletal dyspla sias characterized by stippled epiphyses. A subtype of CDP, X-linked domina nt chondrodysplasia punctata (CDPX2), known also as Conradi-Hunermann-Happl e syndrome, is a rare skeletal dysplasia characterized by short stature, cr aniofacial defects, cataracts, ichthyosis, coarse hair, and alopecia. The c ause of CDPX2 was unknown until recent identification of mutations in the g ene encoding Delta(8),Delta(7) sterol isomerase emopamil-binding protein (E BP). Twelve different EBP mutations have been reported in 14 patients with CDPX2 or unclassified CDP, but with no evidence of correlation between phen otype and nature of the mutation. To characterize additional mutations and investigate possible phenotype-genotype correlation, we sequenced the entir e EBP gene in 8 Japanese individuals with CDP; 5 of them presented with a C DPX2 phenotypes, We found EBP mutations in all 5 CDPX2 individuals, but non e in non-CDPX2 individuals. Three of these CDPX2 individuals carried novel nonsense mutations in EBP and the other two, separate missense mutations th at had been reported also in different ethnic groups. Our results, combined with previous information, suggest all EBP mutations that produce truncate d proteins result in typical CDPX2, whereas the phenotypes resulted from mi ssense mutations are not always typical for CDPX2. Patients with nonsense m utations showed abnormal sterol profiles consistent with a defect in Delta( 8),Delta(7) sterol isomerase, X-inactivation patterns of the patients showe d no skewing, an observation that supports the assumption that inactivation of the EBP gene occurs at random in affected individuals. Am. J. Med. Gene t. 94:300-305, 2000. (C) 2000 Wiley-Liss, Inc.