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. 2004 Jun;74(6):1209-15.
doi: 10.1086/421532. Epub 2004 Apr 29.

Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome

Ilse Wieland  1 , Sibylle Jakubiczka, Petra Muschke, Monika Cohen, Hannelore Thiele, Klaus L Gerlach, Ralf H Adams, Peter Wieacker
Affiliations

Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome

Ilse Wieland et al. Am J Hum Genet. 2004 Jun.

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.

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Figures

Figure 1
Figure 1
Orbital asymmetry in a patient with CFNS
Figure 2
Figure 2
Family 1. A, Pedigree of family 1 with CFNS. B, Deletion of the EFNB1 gene in family 1, detected by Southern blot analysis using exon 2 of the EFNB1 gene as a probe. C, PCR analysis of exons 1–5 of EFNB1. Lane numbers refer to family members depicted in the pedigree.
Figure 3
Figure 3
Family 2. A, Part of the pedigree of family 2. B, Missense mutation 1023C→T in exon 2 of EFNB1 in the hemizygous obligate carrier male (III2) and in an affected heterozygous female. C, PCR analysis and RsaI restriction enzyme cleavage of exon 2 of EFNB1. Lane numbers refer to family members depicted in the pedigree, and the fragments carrying the mutation are indicated by an arrow.
Figure 4
Figure 4
Family 3. A, Part of the pedigree of family 3. B, Missense mutation 862C→T in the hemizygous affected male (I1) and in a heterozygous affected female (III2) of pedigree 3. C, PCR-based detection of the 862C→T mutation in family 3. Lane numbers refer to family members depicted in the pedigree, and the fragments carrying the mutation are indicated by an arrow.
Figure 5
Figure 5
EFNB1 protein and ephrin-B conservation. A, Position of EFNB1 missense mutations that cause CFNS. The mutations are shown on the primary sequence of EFNB1 protein with its signal peptide (SP), transmembrane domain (TM), and cytoplasmic domain (CY). Both missense mutations are located in the ephrin extracellular domain. Deletion Δexon 2–5 is indicated at the cDNA level. B, Evolutionary conservation of P54 and T111 in the ephrin-B class. Domains containing P54 (left column of amino acids) and T111 at the G-H loop (Himanen et al. ; Toth et al. 2001) (right column of amino acids) of human EFNB1-B3 and of EFNB1 protein from mouse (m), rat (r), chicken (c), frog (X), and zebrafish (Dr) are shown.
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References

Electronic-Database Information

    1. Ensembl Genome Server, http://www.ensembl.org (for EFNB1 [accession number ENSP00000204961])
    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank (for EFNB1 reference sequence [accession number XM_038809])
    1. LocusLink, http://www.ncbi.nlm.nih.gov/LocusLink (for EFNB1 [accession number 1947])
    1. NCBI Molecular Variation Database (dbSNP), http://www.ncbi.nlm.nih.gov/SNP
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim

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