Duplication of the EFNB1 gene in familial hypertelorism: imbalance in ephrin-B1 expression and abnormal phenotypes in humans and mice.

Journal article

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: Babbs, C; Stewart, H; Williams, L; Connell, L; Goriely, A

• Publication status: Published
• Journal: Human mutation
• Volume: 32
• Issue: 8
• Pages: 930-938
• Publication date: 2011-08-01
• DOI: 10.1002/humu.21521
• EISSN: 1098-1004
• ISSN: 1059-7794
• Language: English
• Keywords: Mice, Transgenic; Alleles; Child; Genetic Association Studies; Mice; Molecular Sequence Data; Adult; Genotype; Gene Duplication; Ephrin-B1; Sequence Alignment; Humans; Base Sequence; Mice, Inbred C57BL; Middle Aged; Gene Expression Regulation; Pedigree; Phenotype; Female; Hypertelorism; X Chromosome Inactivation; Animals; Chromosomes, Human, X; Transcription, Genetic