title: Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome.
abstract: Craniofrontonasal syndrome (CFNS) is an X-linked craniofacial disorder with an unusual manifestation pattern, in which affected females show multiple skeletal malformations, whereas the genetic defect causes no or only mild abnormalities in male carriers. Recently, we have mapped a gene for CFNS in the pericentromeric region of the X chromosome that contains the EFNB1 gene, which encodes the ephrin-B1 ligand for Eph receptors. Since Efnb1 mutant mice display a spectrum of malformations and an unusual inheritance reminiscent of CFNS, we analyzed the EFNB1 gene in three families with CFNS. In one family, a deletion of exons 2-5 was identified in an obligate carrier male, his mildly affected brother, and in the affected females. In the two other families, missense mutations in EFNB1 were detected that lead to amino acid exchanges P54L and T111I. Both mutations are located in multimerization and receptor-interaction motifs found within the ephrin-B1 extracellular domain. In all cases, mutations were found consistently in obligate male carriers, clinically affected males, and affected heterozygous females. We conclude that mutations in EFNB1 cause CFNS.
authors.affiliation: Institut fur Humangenetik, Otto-von-Guericke-Universitat Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Ilse
authors.initials: I
authors.lastname: Wieland
authors.forename: Sibylle
authors.initials: S
authors.lastname: Jakubiczka
authors.forename: Petra
authors.initials: P
authors.lastname: Muschke
authors.forename: Monika
authors.initials: M
authors.lastname: Cohen
authors.forename: Hannelore
authors.initials: H
authors.lastname: Thiele
authors.forename: Klaus L
authors.initials: KL
authors.lastname: Gerlach
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.forename: Peter
authors.initials: P
authors.lastname: Wieacker
mesh_terms: D000595:Amino Acid Sequence; D041321:Chromosomes, Human, X / Q000235:genetics*; D003398:Craniosynostoses / Q000235:genetics* / Q000473:pathology; D036387:Ephrin-B1 / Q000235:genetics*; D036388:Ephrin-B2 / Q000235:genetics; D036389:Ephrin-B3 / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D013577:Syndrome
chemical_list: D036387:Ephrin-B1; D036388:Ephrin-B2; D036389:Ephrin-B3