title: Skewed X-chromosome inactivation causes intra-familial phenotypic variation of an EBP mutation in a family with X-linked dominant chondrodysplasia punctata.
abstract: X-linked dominant chondrodysplasia punctata (CDPX2) is a skeletal dysplasia characterized by stippled epiphyses, cataracts, alopecia and skin lesions, including ichthyosis. CDPX2 exhibits a number of perplexing clinical features, such as intra- and inter-familial variation, anticipation, incomplete penetrance and possible gonadal and somatic mosaicism. Recently, mutations in the gene encoding Delta8,Delta7 sterol isomerase/emopamil-binding protein (EBP) have been identified in CDPX2. To better understand the genetics of CDPX2, we examined the entire EBP gene by direct sequencing in four CDPX2 patients. We found EBP mutations in all four patients, including three novel mutations: IVS3+1G>A, Y165C and W82C. Surprisingly, a known mutation (R147H) was identified in a patient and her clinically unaffected mother. Expression analysis revealed the mutant allele was predominantly expressed in the patient, while both alleles were expressed in the mother. Methylation analysis revealed that the wild-type allele was predominantly inactivated in the patient, while the mutated allele was predominantly inactivated in her mother. Thus, differences in expression of the mutated allele caused by skewed X-chromosome inactivation produced the diverse phenotypes within the family. Our findings could explain some of the perplexing features of CDPX2. The possibility that an apparently normal parent is a carrier should be considered when examining seemingly sporadic cases and providing genetic counseling to CDPX2 families.
authors.affiliation: Center for Molecular Biology and Cytogenetics, SRL Inc., Hino-shi, Tokyo, Japan.
authors.forename: Shuya
authors.initials: S
authors.lastname: Shirahama
authors.forename: Akira
authors.initials: A
authors.lastname: Miyahara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitoh
authors.forename: Akira
authors.initials: A
authors.lastname: Honda
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kawase
authors.forename: Koki
authors.initials: K
authors.lastname: Yamada
authors.forename: Akihiko
authors.initials: A
authors.lastname: Mabuchi
authors.forename: Hideji
authors.initials: H
authors.lastname: Kura
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Tsutsumi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ikeda
authors.forename: Naomi
authors.initials: N
authors.lastname: Tanaka
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohashi
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
mesh_terms: D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics; D002675:Child, Preschool; D002806:Chondrodysplasia Punctata / Q000097:blood / Q000235:genetics* / Q000473:pathology; D041321:Chromosomes, Human, X / Q000235:genetics*; D019175:DNA Methylation; D004303:Dosage Compensation, Genetic; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage / Q000235:genetics*; D014644:Genetic Variation; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008052:Lipid Metabolism, Inborn Errors / Q000097:blood / Q000235:genetics; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D018010:Receptors, Invertebrate Peptide / Q000235:genetics*; D013261:Sterols / Q000097:blood
chemical_list: D002352:Carrier Proteins; C111344:EGIP-D-binding protein, Anthocidaris crassispina; D018010:Receptors, Invertebrate Peptide; D013261:Sterols