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.

Phenotypes of craniofrontonasal syndrome in patients with a pathogenic mutation in EFNB1

“…A few other features that were not evaluated in this study are presented in the literature: myoclonus, poor hearing, pelvic kidney, bilateral vesico-ureteral reflux, hip girdle anomalies, 11 median cleft lip/palate, 8 asymmetric mandible. 9 Additional features that have been reported in other studies of patients with EFNB1 mutations include: diaphragmatic hernia, 18,19,21,27 dysplastic clavicles and clavicle pseudoarthrosis, [8][9][10][11][12]18,20,23 accessory nipples, 10 high arched palate, 4,9-12,32 uterus arcuatus, 10 duplication of uterus, kidneys and ureters, 10 and low posterior hairline. 8,12,22 Furthermore, some studies state that CFNS patients have a normal intelligence, 8,10,12,15 whereas others claim that some may have learning difficulties to a variable degree.…”

“…[16][17][18] The disease locus was finally claimed to be within Xq13.1 and loss of function mutations in EFNB1 were proven to cause CFNS. 10,[18][19][20][21][22][23][24][25][26][27][28][29][30] EFNB1 encodes ephrin-B1, which is a transmembrane ligand for Eph receptor tyrosine kinases. Because of random X-inactivation heterozygous females are uniquely mosaic and by consequence a cell either does or does not produce a functional protein.…”

“…25 Studies following the discovery of the causal gene predominantly describe the location of new mutations, combined with a brief outline of phenotypic features of small families or cohorts. [18][19][20]22,27,29,30 Detailed overviews of phenotypic features of large cohorts of possible CFNS patients do exist, 3,4,[6][7][8][9][10]12,30 but it is not clear what proportion of these patients carry an EFNB1 mutation. The reports in the older literature could therefore cause confusion by reporting patients who might be improperly classified as CFNS patients.…”

Development of the upper lip: Morphogenetic and molecular mechanisms

“…Genes for several of these have been identified, including PVRL1 in CLP-ectodermal dysplasia syndrome (CLPED1), P63 in dominant ectrodactyly with ectodermal dysplasia and CLP (EEC) and related syndromes, and IRF6 in Van der Woude syndrome (recently reviewed in Cobourne, 2004;Cox, 2004;Marazita and Mooney, 2004). In addition, mutations in E-cadherin (CDH1) were recently found in two families with hereditary diffuse gastric cancer associated with CLP (Frebourg et al, 2005) and mutations in EFNB1 in craniofrontonasal syndrome (CFNS; Twigg et al, 2004;Wieland et al, 2004). Interestingly, PVRL1, P63, IRF6, and CDH1 are all predominantly expressed in epithelial tissues, indicating that proper epithelial differentiation, organization, or patterning play important roles in lip development.…”

Dissecting the molecular mechanisms in craniofrontonasal syndrome: differential mRNA expression of mutant EFNB1 and the cellular mosaic

“…2,3 After detecting the CFNS-causing gene, EFNB1, the model of cellular interference was proposed as the main mechanism responsible for disease manifestation in CFNS females. 1,4 The EFNB1 gene encodes the transmembrane protein ephrin-B1, that functions in bi-directional cell signalling. 5 As a ligand for Eph receptors, ephrin-B1 drives forward signalling in the opposing Eph-expressing cell.…”