title: Duplication of the EFNB1 gene in familial hypertelorism: imbalance in ephrin-B1 expression and abnormal phenotypes in humans and mice.
abstract: Familial hypertelorism, characterized by widely spaced eyes, classically shows autosomal dominant inheritance (Teebi type), but some pedigrees are compatible with X-linkage. No mechanism has been described previously, but clinical similarity has been noted to craniofrontonasal syndrome (CFNS), which is caused by mutations in the X-linked EFNB1 gene. Here we report a family in which females in three generations presented with hypertelorism, but lacked either craniosynostosis or a grooved nasal tip, excluding CFNS. DNA sequencing of EFNB1 was normal, but further analysis revealed a duplication of 937 kb including EFNB1 and two flanking genes: PJA1 and STARD8. We found that the X chromosome bearing the duplication produces ∼1.6-fold more EFNB1 transcript than the normal X chromosome and propose that, in the context of X-inactivation, this difference in expression level of EFNB1 results in abnormal cell sorting leading to hypertelorism. To support this hypothesis, we provide evidence from a mouse model carrying a targeted human EFNB1 cDNA, that abnormal cell sorting occurs in the cranial region. Hence, we propose that X-linked cases resembling Teebi hypertelorism may have a similar mechanism to CFNS, and that cellular mosaicism for different levels of ephrin-B1 (as well as simple presence/absence) leads to craniofacial abnormalities.
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Christian
authors.initials: C
authors.lastname: Babbs
authors.forename: Helen S
authors.initials: HS
authors.lastname: Stewart
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Williams
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Connell
authors.forename: Anne
authors.initials: A
authors.lastname: Goriely
authors.forename: Stephen R F
authors.initials: SR
authors.lastname: Twigg
authors.forename: Kim
authors.initials: K
authors.lastname: Smith
authors.forename: Tracy
authors.initials: T
authors.lastname: Lester
authors.forename: Andrew O M
authors.initials: AO
authors.lastname: Wilkie
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics; D036387:Ephrin-B1 / Q000235:genetics*; D005260:Female; D020440:Gene Duplication / Q000235:genetics*; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D006972:Hypertelorism / Q000175:diagnosis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment; D014158:Transcription, Genetic; D049951:X Chromosome Inactivation
chemical_list: C484288:EFNB1 protein, human; D036387:Ephrin-B1