EFNB1 mutation at the ephrin ligand-receptor dimerization interface in a patient with craniofrontonasal syndrome.

Craniofrontonasal syndrome (CFNS) is characterized by craniosynostosis, hypertelorism, a broad nasal tip and occasionally cleft lip and palate, and is caused by a mutation in the ephrin-B1 gene (EFNB1). The study of naturally occurring human EFNB1 mutations offers a unique opportunity to better define the critical portion within the ephrin domain that is essential for the function of EFNB1 protein in craniofacial development. Here, we report a CFNS patient with a novel EFNB1 missense mutation present at the interface between EFNB1 and its receptor proteins. The patient's facial features included hypertelorism, a broad nasal tip, brachycephaly, frontal bossing, facial asymmetry and esotropia. In addition, she had pectus carinatum, grooved nails on her thumb, an abnormal palmar crease pattern and a broad first toe. Her development was appropriate for her age. Direct sequencing of polymerase chain reaction products using an autosequencer revealed a heterozygous missense mutation, Ser118Ile. Ser118 is located in the G-H loop of the extracellular ephrin domain and is highly evolutionarily conserved among rodents, avians and fish. The mutation occurred de novo and was not present in 100 normal Japanese control subjects. Substitutions of the adjacent amino acid residue, Pro119, have been previously reported in three CFNS patients. Since the structure of EFNB1 is not yet available, the spatial locality of Ser118 was characterized using the protein structure of EFNB2. We deduced that Ser118 in EFNB1 resides at the major dimerization interface with Eph receptors and inferred that the Ser118Ile mutation may impede the protrusion of the G-H loop, thereby disturbing Eph-Ephrin signal transduction.