RBCC Red Blood Cell Collection

EFNB1 (EFL3, EPLG2, LERK2) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Ephrin-B1 (EFL-3; ELK ligand; ELK-L; EPH-related receptor tyrosine kinase ligand 2; LERK-2; Flags: Precursor)

UniProt P98172
ID EFNB1_HUMAN Reviewed; 346 AA.
AC P98172; D3DVU0;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 140.
DE RecName: Full=Ephrin-B1;
DE AltName: Full=EFL-3;
DE AltName: Full=ELK ligand;
DE Short=ELK-L;
DE AltName: Full=EPH-related receptor tyrosine kinase ligand 2;
DE Short=LERK-2;
DE Flags: Precursor;
GN Name=EFNB1; Synonyms=EFL3, EPLG2, LERK2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Placenta;
RX PubMed=8070404;
RA Beckmann M.P., Cerretti D.P., Baum P., Vanden Bos T., James L.,
RA Farrah T., Kozlosky C., Hollingsworth T., Shilling H., Maraskovsky E.,
RA Fletcher F.A., Lhotak V., Pawson T., Lyman S.D.;
RT "Molecular characterization of a family of ligands for eph-related
RT tyrosine kinase receptors.";
RL EMBO J. 13:3757-3762(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7973638; DOI=10.1126/science.7973638;
RA Davis S., Gale N.W., Aldrich T.H., Maisonpierre P.C., Lhotak V.,
RA Pawson T., Goldfarb M., Yancopoulos G.D.;
RT "Ligands for EPH-related receptor tyrosine kinases that require
RT membrane attachment or clustering for activity.";
RL Science 266:816-819(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Fletcher F.A., Huebner K., Shaffer L.G., Monaco A., Mueller U.,
RA Kozlosky C., Druck T., Simoneaux D.K., Fairweather N., Chelly J.,
RA Cerretti D.P., Belmont J.W., Beckmann M.P., Lyman S.D.;
RT "Assignment of the human Elk ligand gene, EPLG2, to chromosome region
RT Xq12.";
RL Submitted (JAN-1997) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PROTEIN SEQUENCE OF 28-42.
RX PubMed=15340161; DOI=10.1110/ps.04682504;
RA Zhang Z., Henzel W.J.;
RT "Signal peptide prediction based on analysis of experimentally
RT verified cleavage sites.";
RL Protein Sci. 13:2819-2824(2004).
RN [8]
RP INTERACTION WITH GRIP1 AND GRIP2.
RC TISSUE=Fetal brain;
RX PubMed=10197531; DOI=10.1016/S0896-6273(00)80706-0;
RA Brueckner K., Pablo Labrador J., Scheiffele P., Herb A., Seeburg P.H.,
RA Klein R.;
RT "EphrinB ligands recruit GRIP family PDZ adaptor proteins into raft
RT membrane microdomains.";
RL Neuron 22:511-524(1999).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-287, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-287, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [11]
RP VARIANTS CFNS LEU-54 AND ILE-111.
RX PubMed=15124102; DOI=10.1086/421532;
RA Wieland I., Jakubiczka S., Muschke P., Cohen M., Thiele H.,
RA Gerlach K.L., Adams R.H., Wieacker P.;
RT "Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome.";
RL Am. J. Hum. Genet. 74:1209-1215(2004).
RN [12]
RP VARIANTS CFNS THR-62; SER-98; PRO-115; HIS-119; THR-119; SER-151;
RP VAL-151; PRO-155; ILE-158 AND VAL-158, AND VARIANT HIS-154.
RX PubMed=15166289; DOI=10.1073/pnas.0402819101;
RA Twigg S.R.F., Kan R., Babbs C., Bochukova E.G., Robertson S.P.,
RA Wall S.A., Morriss-Kay G.M., Wilkie A.O.M.;
RT "Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary
RT formation, cause craniofrontonasal syndrome.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:8652-8657(2004).
RN [13]
RP VARIANTS CFNS ARG-27; LEU-54; SER-119; HIS-119; ALA-137; PHE-138;
RP SER-151; SER-153; TYR-153 AND ARG-182.
RX PubMed=15959873; DOI=10.1002/humu.20193;
RA Wieland I., Reardon W., Jakubiczka S., Franco B., Kress W.,
RA Vincent-Delorme C., Thierry P., Edwards M., Koenig R., Rusu C.,
RA Schweiger S., Thompson E., Tinschert S., Stewart F., Wieacker P.;
RT "Twenty-six novel EFNB1 mutations in familial and sporadic
RT craniofrontonasal syndrome (CFNS).";
RL Hum. Mutat. 26:113-118(2005).
CC -!- FUNCTION: Binds to the receptor tyrosine kinases EPHB1 and EPHA1.
CC Binds to, and induce the collapse of, commissural axons/growth
CC cones in vitro. May play a role in constraining the orientation of
CC longitudinally projecting axons (By similarity).
CC -!- FUNCTION: Cell surface transmembrane ligand for Eph receptors, a
CC family of receptor tyrosine kinases which are crucial for
CC migration, repulsion and adhesion during neuronal, vascular and
CC epithelial development. Binds promiscuously Eph receptors residing
CC on adjacent cells, leading to contact-dependent bidirectional
CC signaling into neighboring cells. The signaling pathway downstream
CC of the receptor is referred to as forward signaling while the
CC signaling pathway downstream of the ephrin ligand is referred to
CC as reverse signaling. Binds to the receptor tyrosine kinases EPHB3
CC (preferred), EPHB1 and EPHA1. Binds to, and induce the collapse
CC of, commissural axons/growth cones in vitro. May play a role in
CC constraining the orientation of longitudinally projecting axons
CC (By similarity).
CC -!- SUBUNIT: Interacts with GRIP1 and GRIP2.
CC -!- INTERACTION:
CC P04626:ERBB2; NbExp=11; IntAct=EBI-538287, EBI-641062;
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein.
CC -!- TISSUE SPECIFICITY: Heart, placenta, lung, liver, skeletal muscle,
CC kidney, pancreas.
CC -!- INDUCTION: By TNF.
CC -!- PTM: Inducible phosphorylation of tyrosine residues in the
CC cytoplasmic domain (By similarity).
CC -!- DISEASE: Craniofrontonasal syndrome (CFNS) [MIM:304110]: X-linked
CC inherited syndrome characterized by hypertelorism, coronal
CC synostosis with brachycephaly, downslanting palpebral fissures,
CC clefting of the nasal tip, joint anomalies, longitudinally grooved
CC fingernails and other digital anomalies. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the ephrin family.
CC -!- SIMILARITY: Contains 1 ephrin RBD (ephrin receptor-binding)
CC domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/EFNB1";
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DR EMBL; U09304; AAA53093.1; -; mRNA.
DR EMBL; L37361; AAA52369.1; -; mRNA.
DR EMBL; U09303; AAB41127.1; -; mRNA.
DR EMBL; AL136092; CAB86409.1; -; Genomic_DNA.
DR EMBL; CH471132; EAX05370.1; -; Genomic_DNA.
DR EMBL; CH471132; EAX05371.1; -; Genomic_DNA.
DR EMBL; BC016649; AAH16649.1; -; mRNA.
DR EMBL; BC052979; AAH52979.1; -; mRNA.
DR PIR; S46993; S46993.
DR RefSeq; NP_004420.1; NM_004429.4.
DR UniGene; Hs.144700; -.
DR ProteinModelPortal; P98172; -.
DR SMR; P98172; 32-167.
DR IntAct; P98172; 10.
DR STRING; 9606.ENSP00000204961; -.
DR PhosphoSite; P98172; -.
DR DMDM; 1706668; -.
DR PaxDb; P98172; -.
DR PeptideAtlas; P98172; -.
DR PRIDE; P98172; -.
DR DNASU; 1947; -.
DR Ensembl; ENST00000204961; ENSP00000204961; ENSG00000090776.
DR GeneID; 1947; -.
DR KEGG; hsa:1947; -.
DR UCSC; uc004dxd.4; human.
DR CTD; 1947; -.
DR GeneCards; GC0XP068048; -.
DR HGNC; HGNC:3226; EFNB1.
DR HPA; CAB031489; -.
DR MIM; 300035; gene.
DR MIM; 304110; phenotype.
DR neXtProt; NX_P98172; -.
DR Orphanet; 1520; Craniofrontonasal dysplasia.
DR PharmGKB; PA27661; -.
DR eggNOG; NOG262190; -.
DR HOGENOM; HOG000220931; -.
DR HOVERGEN; HBG051448; -.
DR InParanoid; P98172; -.
DR KO; K05463; -.
DR OMA; PDSFFNS; -.
DR OrthoDB; EOG7288S5; -.
DR PhylomeDB; P98172; -.
DR SignaLink; P98172; -.
DR ChiTaRS; EFNB1; human.
DR GeneWiki; EFNB1; -.
DR GenomeRNAi; 1947; -.
DR NextBio; 7891; -.
DR PMAP-CutDB; P98172; -.
DR PRO; PR:P98172; -.
DR Bgee; P98172; -.
DR CleanEx; HS_EFNB1; -.
DR Genevestigator; P98172; -.
DR GO; GO:0005737; C:cytoplasm; IEA:Ensembl.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0045202; C:synapse; ISS:UniProtKB.
DR GO; GO:0046875; F:ephrin receptor binding; TAS:ProtInc.
DR GO; GO:0007411; P:axon guidance; IEA:Ensembl.
DR GO; GO:0007155; P:cell adhesion; TAS:ProtInc.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:0009880; P:embryonic pattern specification; IEA:Ensembl.
DR GO; GO:0001755; P:neural crest cell migration; IEA:Ensembl.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IEA:Ensembl.
DR Gene3D; 2.60.40.420; -; 1.
DR InterPro; IPR008972; Cupredoxin.
DR InterPro; IPR001799; Ephrin.
DR InterPro; IPR019765; Ephrin_CS.
DR PANTHER; PTHR11304; PTHR11304; 1.
DR Pfam; PF00812; Ephrin; 1.
DR PRINTS; PR01347; EPHRIN.
DR ProDom; PD002533; Ephrin; 1.
DR SUPFAM; SSF49503; SSF49503; 1.
DR PROSITE; PS01299; EPHRIN_RBD_1; 1.
DR PROSITE; PS51551; EPHRIN_RBD_2; 1.
PE 1: Evidence at protein level;
KW Complete proteome; Developmental protein; Differentiation;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Glycoprotein; Membrane; Neurogenesis; Phosphoprotein; Polymorphism;
KW Reference proteome; Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1 27
FT CHAIN 28 346 Ephrin-B1.
FT /FTId=PRO_0000008387.
FT TOPO_DOM 28 237 Extracellular (Potential).
FT TRANSMEM 238 258 Helical; (Potential).
FT TOPO_DOM 259 346 Cytoplasmic (Potential).
FT DOMAIN 30 164 Ephrin RBD.
FT MOTIF 344 346 PDZ-binding (Potential).
FT MOD_RES 287 287 Phosphoserine.
FT CARBOHYD 139 139 N-linked (GlcNAc...) (Potential).
FT DISULFID 64 101 By similarity.
FT DISULFID 89 153 By similarity.
FT VARIANT 27 27 P -> R (in CFNS).
FT /FTId=VAR_023127.
FT VARIANT 54 54 P -> L (in CFNS).
FT /FTId=VAR_023128.
FT VARIANT 62 62 I -> T (in CFNS).
FT /FTId=VAR_023129.
FT VARIANT 98 98 L -> S (in CFNS).
FT /FTId=VAR_023130.
FT VARIANT 111 111 T -> I (in CFNS).
FT /FTId=VAR_023131.
FT VARIANT 115 115 Q -> P (in CFNS).
FT /FTId=VAR_023132.
FT VARIANT 119 119 P -> H (in CFNS).
FT /FTId=VAR_023133.
FT VARIANT 119 119 P -> S (in CFNS).
FT /FTId=VAR_023134.
FT VARIANT 119 119 P -> T (in CFNS).
FT /FTId=VAR_023135.
FT VARIANT 137 137 T -> A (in CFNS).
FT /FTId=VAR_023136.
FT VARIANT 138 138 S -> F (in CFNS).
FT /FTId=VAR_023137.
FT VARIANT 151 151 G -> S (in CFNS; dbSNP:rs28936069).
FT /FTId=VAR_023138.
FT VARIANT 151 151 G -> V (in CFNS; dbSNP:rs28936070).
FT /FTId=VAR_023139.
FT VARIANT 153 153 C -> S (in CFNS).
FT /FTId=VAR_023140.
FT VARIANT 153 153 C -> Y (in CFNS).
FT /FTId=VAR_023141.
FT VARIANT 154 154 R -> H.
FT /FTId=VAR_023142.
FT VARIANT 155 155 T -> P (in CFNS).
FT /FTId=VAR_023143.
FT VARIANT 158 158 M -> I (in CFNS; dbSNP:rs28935170).
FT /FTId=VAR_023144.
FT VARIANT 158 158 M -> V (in CFNS; dbSNP:rs28936071).
FT /FTId=VAR_023145.
FT VARIANT 172 172 T -> M (in dbSNP:rs7889678).
FT /FTId=VAR_059256.
FT VARIANT 182 182 S -> R (in CFNS).
FT /FTId=VAR_023146.
FT VARIANT 189 189 V -> A (in dbSNP:rs16989105).
FT /FTId=VAR_023147.
SQ SEQUENCE 346 AA; 38007 MW; 473DD2F1A5BF89DE CRC64;
MARPGQRWLG KWLVAMVVWA LCRLATPLAK NLEPVSWSSL NPKFLSGKGL VIYPKIGDKL
DIICPRAEAG RPYEYYKLYL VRPEQAAACS TVLDPNVLVT CNRPEQEIRF TIKFQEFSPN
YMGLEFKKHH DYYITSTSNG SLEGLENREG GVCRTRTMKI IMKVGQDPNA VTPEQLTTSR
PSKEADNTVK MATQAPGSRG SLGDSDGKHE TVNQEEKSGP GASGGSSGDP DGFFNSKVAL
FAAVGAGCVI FLLIIIFLTV LLLKLRKRHR KHTQQRAAAL SLSTLASPKG GSGTAGTEPS
DIIIPLRTTE NNYCPHYEKV SGDYGHPVYI VQEMPPQSPA NIYYKV
//

MIM 300035
*RECORD*
*FIELD* NO
300035
*FIELD* TI
*300035 EPHRIN B1; EFNB1
;;EPH-RELATED RECEPTOR TYROSINE KINASE LIGAND 2; EPLG2;;
LIGAND OF EPH-RELATED KINASE 2; LERK2;;
read moreEFL3
*FIELD* TX

DESCRIPTION

See 179610 for background information on ephrins and the Eph family of
receptor protein-tyrosine kinases. The EFNB1 gene encodes a ligand of
ELK (EPHB1; 600600) that is highly conserved among rat, mouse, and
human.

GENE FUNCTION

Bohme et al. (1996) presented evidence that LERK2 is a functional ligand
of the EPH-related kinase HEK2 (EPHB3; 601839). They reported that
coincubation of HEK2- and LERK2-expressing cells induces cell-cell
adhesion and aggregation.

Palmer et al. (2002) showed that SRC family kinases, or SFKs (see SRC;
190090), are positive regulators of ephrin-B phosphorylation and
phosphotyrosine-mediated reverse signaling. EphB receptor engagement of
ephrin-B caused rapid recruitment of SFKs to ephrin-B expression domains
and transient SFK activation. With delayed kinetics, ephrin-B ligands
recruited the cytoplasmic PDZ domain-containing protein tyrosine
phosphatase PTPBL (see 600267) and were dephosphorylated. These data
suggested the presence of a switch mechanism that allows a shift from
phosphotyrosine-/SFK-dependent signaling to PDZ-dependent signaling.

Batlle et al. (2002) showed that beta-catenin (116806) and TCF (see
TCF7L2; 602228) inversely control the expression of the EphB2
(600997)/EphB3 receptors and their ligand, ephrin B1, in colorectal
cancer and along the crypt-villus axis. Disruption of EphB2 and EphB3
genes revealed that their gene products restrict cell intermingling and
allocate cell populations within the intestinal epithelium. In
EphB2/EphB3 null mice, the proliferative and differentiated populations
intermingled. In adult EphB3 -/- mice, Paneth cells did not follow their
downward migratory path, but scattered along crypt and villus. The
authors concluded that, in the intestinal epithelium, beta-catenin and
TCF couple proliferation and differentiation to the sorting of cell
populations through the EphB/ephrin B system.

Moore et al. (2004) studied the role of FGF and ephrin signaling in
retina development in the frog. Activation of Fgfr2 (176943) signaling
before gastrulation repressed cellular movements in the presumptive
anterior neural plate and prevented normal retinal progenitor cells from
adopting retinal fates. Ephrin B1 signaling during gastrulation was
required for retinal progenitors to move into the eye field, and this
movement could be modified by activating the FGF pathway. Moore et al.
(2004) concluded that FGF modulation of ephrin signaling is important
for establishing the bona fide retinal progenitors in the anterior
neural plate.

Egawa et al. (2003) examined the expression of B class ephrins-Ephs in
the human ovary during corpus luteum formation, a process of tissue
remodeling accompanied by angiogenesis. RT-PCR analysis detected mRNA of
ephrins B1 and B2 (600527) and EPHB1 (600600), EPHB2, and EPHB4 (600011)
in human corpora lutea of the early luteal phase. After ovulation, a
rapid increase in ephrin B1 expression was observed on luteinizing
granulosa cells, whereas its expression on luteinizing theca interna
cells decreased. The authors concluded that ephrin B1-expressing
granulosa cells can directly interact with Eph-bearing cells during
corpus luteum formation in vivo, suggesting that Eph-ephrin system is
involved in this process.

Bong et al. (2007) found that vertebrate ephrin B1 interacted with Stat3
(102582) in a tyrosine phosphorylation-dependent manner, resulting in
phosphorylation and enhanced transcriptional activation of Stat3.

Using Xenopus oocytes, Lee et al. (2008) showed that ephrin B1
colocalized with the Par polarity complex protein Par6 (PARD6A; 607484),
a scaffold protein required for establishing tight junctions. Reciprocal
immunoprecipitation analysis confirmed direct interaction of endogenous
PAR6 and ephrin B1 in human colon cancer cells and in Xenopus oocytes.
Ephrin B1 competed with Cdc42 (116952) for association with Par6 in
Xenopus oocytes, which caused inactivation of the Par complex and loss
of tight junctions. The interaction between ephrin B1 and Par6 was
disrupted by tyrosine phosphorylation of the intracellular domain of
ephrin B1, which occurs upon binding an Eph receptor or the tight
junction-associated protein claudin (see CLDN1; 603718) or in response
to FGF receptor activation. Lee et al. (2008) concluded that ephrin
B1-induced displacement of active CDC42 from PAR6 disrupts tight
junctions, and that tyrosine phosphorylation of ephrin B1 inhibits
ephrin B1-PAR6 interactions, resulting in the proper establishment of
tight junctions.

Jorgensen et al. (2009) implemented a proteomic strategy to
systematically determine cell-specific signaling networks underlying
EphB2- and ephrin-B1-controlled cell sorting. Quantitative mass
spectrometric analysis of mixed populations of EphB2- and
ephrin-B1-expressing cells that were labeled with different isotopes
revealed cell-specific tyrosine phosphorylation events. Functional
associations between these phosphotyrosine signaling networks and cell
sorting were established with small interfering RNA screening.
Data-driven network modeling revealed that signaling between mixed
EphB2- and ephrin-B1-expressing cells is asymmetric and that the
distinct cell types use different tyrosine kinases and targets to
process signals induced by cell-cell contact. Jorgensen et al. (2009)
provided systems- and cell-specific network models of contact-initiated
signaling between 2 distinct cell types.

GENE STRUCTURE

The EFNB1 gene comprises 13.17 kb and 5 exons (Wieland et al., 2004).

MAPPING

Eplg2 was mapped by Fletcher et al. (1994) to the central portion of the
mouse X chromosome, tightly linked to the androgen receptor (AR; 313700)
locus. Mapping to this locus predicted that the human homolog, EPLG2,
would map near human AR, in the interval Xq11-q12. To confirm this
prediction and to localize EPLG2 to a 200-kb interval in Xq12, Fletcher
et al. (1995) used Southern blot analysis of genomic DNAs from a
rodent-human somatic cell hybrid mapping panel, 2-color fluorescence in
situ hybridization, and YAC hybridization.

MOLECULAR GENETICS

Craniofrontonasal syndrome (CFNS; 304110) 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, such as
hypertelorism (Saavedra et al., 1996). A locus for CFNS maps to the
centromeric region of the X chromosome (Xq12) where the EFNB1 gene is
located. Because of the spectrum of malformations in Efnb1 mice and the
unusual inheritance pattern reminiscent of CFNS (Compagni et al., 2003),
Wieland et al. (2004) analyzed the EFNB1 gene in 3 families with CFNS.
One family had a deletion of exons 2-5 (300035.0001); the 2 other
families had missense mutations. Both missense mutations were 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.

Twigg et al. (2004) showed that the classic female CFNS phenotype is
caused by heterozygous loss-of-function mutation in the EFNB1 gene. In
24 affected females from 20 unrelated families, they identified 17
different mutations (see 300035.0004-300035.0007). One of the mutations,
gly151 to ser (G151S; 300035.0004), was identified in 4 families. A
mutation at the same codon, gly151 to val (G151V; 300035.0005), was also
identified in a de novo case. In mice, the orthologous Efnb1 gene is
expressed in the frontonasal neural crest and demarcates the position of
the future coronal suture. Although EFNB1 is X-inactivated, Twigg et al.
(2004) did not observe markedly skewed X inactivation in either blood or
cranial periosteum from females with CFNS, indicating that lack of
ephrin-B1 does not compromise cell viability in these tissues. Twigg et
al. (2004) proposed that in heterozygous females, patchwork loss of
ephrin-B1 disturbs tissue boundary formation at the developing coronal
suture, whereas in males deficient in ephrin-B1, an alternative
mechanism maintains the normal boundary. They stated that this was the
only known mutation in the ephrin/EPH receptor signaling system in
humans and that it provided clues to the biogenesis of craniosynostosis.

Among 38 unrelated patients with CFNS, Wieland et al. (2005) identified
33 different mutations in the EFNB1 gene, including 26 novel mutations.
Nine cases were familial, and 29 cases were sporadic.

CFNS is an X-linked disorder that exhibits a paradoxical sex reversal in
phenotypic severity: females characteristically have frontonasal
dysplasia, craniosynostosis, and additional minor malformations, but
males are usually mildly affected with hypertelorism only. Despite this,
males appear underrepresented in CFNS pedigrees, with carrier males
encountered infrequently compared with affected females. To investigate
these unusual genetic features of CFNS, Twigg et al. (2006) exploited
the recent discovery of causative mutations in the EFNB1 gene to survey
the molecular alterations in 59 families (39 newly investigated and 20
published elsewhere). They identified the first complete deletions of
EFNB1, cataloged 27 novel intragenic mutations, and used pyrosequencing
and analysis of nearby polymorphic alleles to quantify mosaic cases and
to determine the parental origin of verified germline mutations. Somatic
mosaicism was demonstrated in 6 of 53 informative families, and, of 17
germline mutations in individuals for whom the parental origin of
mutation could be demonstrated, 15 arose from the father. Twigg et al.
(2006) concluded that the major factor accounting for the relative
scarcity of carrier males is the bias toward mutations in the paternal
germline (which present as affected female offspring) combined with
reduced reproductive fitness in affected females. Postzygotic mutations
also contributed to the female preponderance, whereas true nonpenetrance
in males who are hemizygous for an EFNB1 mutation appeared unusual.

Wieland et al. (2007) identified mutations in the EFNB1 gene in 10 of 13
patients with CFNS. The 3 remaining patients had contiguous gene
deletions involving EFNB1 and the neighboring genes OPHN1 (300127), PJA1
(300420), and EDA (300451).

Wieland et al. (2008) showed that cultured fibroblasts derived from
female patients with heterozygous EFNB1 mutations expressed both mutant
and wildtype EFNB1 and that upon clonal expansion it was possible to
separate mutant and wildtype EFNB1-expressing cells in vitro, indicating
2 distinct cell populations with respect to EFNB1 gene function. These
results supported cellular interference as being the cause of the more
severe phenotype in CFNS females. Such a situation does not occur in
hemizygous carrier males, who are mildly affected.

ANIMAL MODEL

Compagni et al. (2003) reported that targeted inactivation of the
X-linked gene Efnb1 in mice caused partial perinatal lethality,
abdominal wall closure defects, and skeletal abnormalities, especially
of the thoracic cage. The phenotype was more severe in female
heterozygotes than in hemizygous males, and some defects, such as
preaxial polydactyly, were detected only in heterozygotes.

Davy et al. (2004) found that complete ablation of ephrin B1 in mice
resulted in perinatal lethality associated with a range of phenotypes,
including defects in neural crest cell-derived tissues, incomplete body
wall closure, and abnormal skeletal patterning. Conditional deletion of
ephrin B1 in neural crest cells indicated that ephrin B1 controls
migration in this cell population. The authors provided evidence that
ephrin B1 acts both as a ligand and as a receptor in a tissue-specific
manner during embryogenesis.

*FIELD* AV
.0001
CRANIOFRONTONASAL SYNDROME
EFNB1, EX2-5DEL

In a family with craniofrontonasal syndrome (304110), Wieland et al.
(2004) found that an obligate carrier male, his mildly affected brother,
and 2 affected females carried a deletion of exons 2-5 in the EFNB1
gene. The affected females exhibited typical features of CFNS, including
hypertelorism and craniofacial abnormalities such as orbital asymmetry.
All were normal in their mental performance and showed no behavioral
abnormalities. Body height was also in the normal range.

.0002
CRANIOFRONTONASAL SYNDROME
EFNB1, THR111ILE

In affected members of a family in which 6 females in 5 generations had
craniofrontonasal syndrome (304110) and 3 males were hemizygous
carriers, Wieland et al. (2004) found a thr111-to-ile (T111I) mutation
that was the result of a 1023C-T transition in the EFNB1 gene. The
phenotypes of the patients included hypertelorism, orbital asymmetry,
brachycephaly, brachydactyly, and Sprengel deformity (184400). One
affected female had experienced 4 miscarriages in midpregnancy and was
found to have uterus arcuatus. In addition she had curly hair, grooved
fingernails, and unilateral breast hypoplasia.

.0003
CRANIOFRONTONASAL SYNDROME
EFNB1, PRO54LEU

In a family in which a mother and daughter had craniofrontonasal
syndrome (304110) and the maternal grandfather was asymptomatic
hemizygote, Wieland et al. (2004) found a pro54-to-leu (P54L) mutation
resulting from an 862C-T transition in the EFNB1 gene. The grandfather
showed only slight facial asymmetry and a broad nasal bridge. His
daughter showed severe facial asymmetry, hypertelorism, and hypoplasia
of the corpus callosum. The granddaughter exhibited facial asymmetry,
hypertelorism, agenesis of the corpus callosum, complete syndactyly of
the third and fourth finger on the left side, and scoliosis.

.0004
CRANIOFRONTONASAL SYNDROME
EFNB1, GLY151SER

In affected members of 4 unrelated families with craniofrontonasal
syndrome (304110), Twigg et al. (2004) identified a 451G-A transition
within a CpG doublet in exon 3 of the EFNB1 gene, resulting in a
gly151-to-ser (G151S) mutation. The mutation was transmitted by an
affected mother to her daughter in at least 1 instance.

.0005
CRANIOFRONTONASAL SYNDROME
EFNB1, GLY151VAL

In a de novo case of craniofrontonasal syndrome (304110), Twigg et al.
(2004) identified a 452G-T transversion in exon 3 of the EFNB1 gene,
resulting in a gly151-to-val (G151V) substitution.

.0006
CRANIOFRONTONASAL SYNDROME
EFNB1, MET158VAL

In a familial case of craniofrontonasal syndrome (304110), Twigg et al.
(2004) identified a 472A-G transition in exon 3 of the EFNB1 gene,
resulting in a met158-to-val (M158V) substitution.

.0007
CRANIOFRONTONASAL SYNDROME
EFNB1, MET158ILE

In a familial case of craniofrontonasal syndrome (304110), Twigg et al.
(2004) identified a 474G-T transversion in exon 3 of the EFNB1 gene,
resulting in a met158-to-ile (M158I) substitution.

.0008
CRANIOFRONTONASAL SYNDROME
EFNB1, TRP37GLY

In 2 unrelated female probands with CFNS (304110), Twigg et al. (2006)
found a trp37-to-gly (W37G) mutation in the EFNB1 gene. In another
family, 1 female and 1 male were found to have a nonsense mutation in
the same codon, trp37 to stop (W37X; 300035.0009).

.0009
CRANIOFRONTONASAL SYNDROME
EFNB1, TRP37TER

See 300035.0008 and Twigg et al. (2006).

.0010
CRANIOFRONTONASAL SYNDROME
EFNB1, ARG66TER

In 3 unrelated female probands with craniofrontonasal syndrome (304110),
Twigg et al. (2006) identified an arg66-to-stop (R66X) mutation in the
EFNB1 gene.

*FIELD* RF
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W.; Sancho, E.; Huls, G.; Meeldijk, J.; Robertson, J.; van de Wetering,
M.; Pawson, T.; Clevers, H.: Beta-catenin and TCF mediate cell positioning
in the intestinal epithelium by controlling the expression of EphB/EphrinB. Cell 111:
251-263, 2002.

2. Bohme, B.; VandenBos, T.; Cerretti, D. P.; Park, L. S.; Holtrich,
U.; Rubsamen-Waigmann, H.; Strebhardt, K.: Cell-cell adhesion mediated
by binding of membrane-anchored ligand LERK-2 to the EPH-related receptor
human embryonal kinase 2 promotes tyrosine kinase activity. J. Biol.
Chem. 271: 24747-24752, 1996.

3. Bong, Y.-S.; Lee, H.-S.; Carim-Todd, L.; Mood, K.; Nishanian, T.
G.; Tessarollo, L.; Daar, I. O.: ephrinB1 signals from the cell surface
to the nucleus by recruitment of STAT3. Proc. Nat. Acad. Sci. 104:
17305-17310, 2007.

4. Compagni, A.; Logan, M.; Klein, R.; Adams, R. H.: Control of skeletal
patterning by ephrinB1-EphB interactions. Dev. Cell 5: 217-230,
2003.

5. Davy, A.; Aubin, J.; Soriano, P.: Ephrin-B1 forward and reverse
signaling are required during mouse development. Genes Dev. 18:
572-583, 2004.

6. Egawa, M.; Yoshioka, S.; Higuchi, T.; Sato, Y.; Tatsumi, K.; Fujiwara,
H.; Fujii, S.: Ephrin B1 is expressed on human luteinizing granulosa
cells in corpora lutea of the early luteal phase: the possible involvement
of the B class eph-ephrin system during corpus luteum formation. J.
Clin. Endocr. Metab. 88: 4384-4392, 2003.

7. Fletcher, F. A.; Huebner, K.; Shaffer, L. G.; Fairweather, N. D.;
Monaco, A. P.; Muller, U.; Druck, T.; Simoneaux, D. K.; Chelly, J.;
Belmont, J. W.; Beckmann, M. P.; Lyman, S. D.: Assignment of the
gene (EPLG2) encoding a high-affinity binding protein for the receptor
tyrosine kinase Elk to a 200-kilobasepair region in human chromosome
Xq12. Genomics 25: 334-335, 1995.

8. Fletcher, F. A.; Renshaw, B.; Hollingsworth, T.; Baum, P.; Lyman,
S. D.; Jenkins, N. A.; Gilbert, D. J.; Copeland, N. G.; Davison, B.
L.: Genomic organization and chromosomal localization of mouse Eplg2,
a gene encoding a binding protein for the receptor tyrosine kinase
Elk. Genomics 24: 127-132, 1994.

9. Jorgensen, C.; Sherman, A.; Chen, G. I.; Pasculescu, A.; Poliakov,
A.; Hsiung, M.; Larsen, B.; Wilkinson, D. G.; Linding, R.; Pawson,
T.: Cell-specific information processing in segregating populations
of Eph receptor ephrin-expressing cells. Science 326: 1502-1509,
2009.

10. Lee, H.-S.; Nishanian, T. G.; Mood, K.; Bong, Y.-S.; Daar, I.
O.: EphrinB1 controls cell-cell junctions through the Par polarity
complex. Nature Cell Biol. 10: 979-986, 2008.

11. Moore, K. B.; Mood, K.; Daar, I. O.; Moody, S. A.: Morphogenetic
movements underlying eye field formation require interactions between
the FGF and ephrinB1 signaling pathways. Dev. Cell 6: 55-67, 2004.

12. Palmer, A.; Zimmer, M.; Erdmann, K. S.; Eulenburg, V.; Porthin,
A.; Heumann, R.; Deutsch, U.; Klein, R.: EphrinB phosphorylation
and reverse signaling: regulation by Src kinases and PTP-BL phosphatase. Molec.
Cell 9: 725-737, 2002.

13. Saavedra, D.; Richieri-Costa, A.; Guion-Almeida, M. L.; Cohen,
M. M., Jr.: Craniofrontonasal syndrome: study of 41 patients. Am.
J. Med. Genet. 61: 147-151, 1996.

14. Twigg, S. R. F.; Kan, R.; Babbs, C.; Bochukova, E. G.; Robertson,
S. P.; Wall, S. A.; Morriss-Kay, G. M.; Wilkie, A. O. M.: Mutations
of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause
craniofrontonasal syndrome. Proc. Nat. Acad. Sci. 101: 8652-8657,
2004.

15. Twigg, S. R. F.; Matsumoto, K.; Kidd, A. M. J.; Goriely, A.; Taylor,
I. B.; Fisher, R. B.; Hoogeboom, A. J. M.; Mathijssen, I. M. J.; Lourenco,
M. T.; Morton, J. E. V.; Sweeney, E.; Wilson, L. C.; Brunner, H. G.;
Mulliken, J. B.; Wall, S. A.; Wilkie, A. O. M.: The origin of EFNB1
mutations in craniofrontonasal syndrome: frequent somatic mosaicism
and explanation of the paucity of carrier males. Am. J. Hum. Genet. 78:
999-1010, 2006.

16. Wieland, I.; Jakubiczka, S.; Muschke, P.; Cohen, M.; Thiele, H.;
Gerlach, K. L.; Adams, R. H.; Wieacker, P.: Mutations of the ephrin-B1
gene cause craniofrontonasal syndrome. Am. J. Hum. Genet. 74: 1209-1215,
2004.

17. Wieland, I.; Makarov, R.; Reardon, W.; Tinschert, S.; Goldenberg,
A.; Thierry, P.; Wieacker, P.: Dissecting the molecular mechanisms
in craniofrontonasal syndrome: differential mRNA expression of mutant
EFNB1 and the cellular mosaic. Europ. J. Hum. Genet. 16: 184-191,
2008.

18. Wieland, I.; Reardon, W.; Jakubiczka, S.; Franco, B.; Kress, W.;
Vincent-Delorme, C.; Thierry, P.; Edwards, M.; Konig, R.; Rusu, C.;
Schweiger, S.; Thompson, E.; Tinschert, S.; Stewart, F.; Wieacker,
P.: Twenty-six novel EFNB1 mutations in familial and sporadic craniofrontonasal
syndrome (CFNS). Hum. Mutat. 26: 113-118, 2005.

19. Wieland, I.; Weidner, C.; Ciccone, R.; Lapi, E.; McDonald-McGinn,
D.; Kress, W.; Jakubiczka, S.; Collmann, H.; Zuffardi, O.; Zackai,
E.; Wieacker, P.: Contiguous gene deletions involving EFNB1, OPHN1,
PJA1 and EDA in patients with craniofrontonasal syndrome. Clin. Genet. 72:
506-516, 2007.

*FIELD* CN
Cassandra L. Kniffin - updated: 1/26/2010
Ada Hamosh - updated: 1/6/2010
Patricia A. Hartz - updated: 8/31/2009
Patricia A. Hartz - updated: 8/20/2008
Cassandra L. Kniffin - updated: 1/10/2008
Cassandra L. Kniffin - updated: 8/14/2006
Victor A. McKusick - updated: 5/15/2006
John A. Phillips, III - updated: 7/6/2005
Victor A. McKusick - updated: 7/13/2004
Victor A. McKusick - updated: 5/20/2004
Patricia A. Hartz - updated: 5/12/2004
Patricia A. Hartz - updated: 4/21/2004
Stylianos E. Antonarakis - updated: 12/3/2002
Stylianos E. Antonarakis - updated: 9/20/2002

*FIELD* CD
Victor A. McKusick: 2/25/1996

*FIELD* ED
wwang: 02/05/2010
ckniffin: 1/26/2010
alopez: 1/15/2010
terry: 1/6/2010
mgross: 9/8/2009
terry: 8/31/2009
carol: 5/11/2009
mgross: 8/20/2008
terry: 8/20/2008
ckniffin: 1/10/2008
carol: 1/31/2007
wwang: 8/23/2006
ckniffin: 8/14/2006
alopez: 5/17/2006
terry: 5/15/2006
alopez: 7/6/2005
tkritzer: 7/28/2004
tkritzer: 7/19/2004
terry: 7/13/2004
alopez: 5/24/2004
terry: 5/20/2004
mgross: 5/12/2004
mgross: 4/21/2004
mgross: 12/3/2002
mgross: 9/20/2002
psherman: 7/14/1998
psherman: 4/23/1998
psherman: 4/20/1998
alopez: 6/5/1997
mark: 11/25/1996
joanna: 2/25/1996

MIM 304110
*RECORD*
*FIELD* NO
304110
*FIELD* TI
#304110 CRANIOFRONTONASAL SYNDROME; CFNS
;;CRANIOFRONTONASAL DYSPLASIA; CFND;;
CRANIOFRONTONASAL DYSOSTOSIS
read more*FIELD* TX
A number sign (#) is used with this entry because craniofrontonasal
syndrome (CFNS) can be caused by mutation in the EFNB1 gene (300035) on
chromosome Xq12.

DESCRIPTION

Craniofrontonasal syndrome is an X-linked developmental disorder that
shows paradoxically greater severity in heterozygous females than in
hemizygous males. Females have frontonasal dysplasia, craniofacial
asymmetry, craniosynostosis, bifid nasal tip, grooved nails, wiry hair,
and abnormalities of the thoracic skeleton, whereas males typically show
only hypertelorism (Twigg et al., 2004; Wieland et al., 2004).

CLINICAL FEATURES

Cohen (1979) identified CFNS as a subgroup of frontonasal dysplasia.
CFNS is characterized in females by hypertelorism, coronal
craniosynostosis, craniofacial asymmetry, frontal bossing, downslanting
palpebral fissures, clefting of the nasal tip, longitudinally grooved
fingernails, and other digital anomalies (Vasudevan et al., 2006).

Pruzansky et al. (1982) described an extensively affected family in
which 14 females and 1 male had CFNS. Morris et al. (1987) described a
4-generation family in which 6 persons had frontonasal dysplasia with
variable extracranial abnormalities. All affected persons had
hypertelorism, bifid or broad nose, and highly arched palate. Cleft lip
and palate were present in 1, Sprengel anomaly in 2, pseudarthrosis of
the clavicle in 2, pectus excavatum in 3, diaphragmatic hernia in 2,
broad first toe in 4, longitudinal grooves of the nails in 5, shawl
scrotum in 2 of 3 males, 1 of whom had first-degree hypospadias, and
mild retardation in 1. McGaughran et al. (2002) suggested that the
family reported by Morris et al. (1987) may instead have had
brachycephalofrontonasal dysplasia (Teebi syndrome; 145420), since the
affected males demonstrated additional anomalies not usually observed in
CFNS.

Morris et al. (1987) reviewed reported families, including those of
Reynolds et al. (1982), Slover and Sujansky (1979), and Pruzansky et al.
(1982). All daughters of affected males were affected, a finding
consistent with X-linked dominant inheritance.

Hurst and Baraitser (1988) confirmed the female preponderance in this
condition and noted that all their patients had thick, wiry hair. Smith
et al. (1989) described a 3-generation family. In addition to the
coronal craniosynostosis and facial changes, syndactyly of fingers and
toes and longitudinally grooved nails were present. More mildly affected
males did not have craniosynostosis but did show hypertelorism, broad
great toes, and grooved nails. Smith et al. (1989) provided follow-up of
the family reported by Slover and Sujansky (1979); 5 daughters were all
affected, whereas 3 sons were all normal.

Since there is no evidence of tissue dysplasia in CFNS, Michels et al.
(1989) suggested that the disorder be designated craniofrontonasal
dysostosis. They reported an affected mother and daughter who also had
limited hip and shoulder abduction. In addition, the mother had axillary
pterygia, congenital footplate fixation of the left ear, right
sensorineural hearing loss, and limited forearm pronation. Kapusta et
al. (1992) reported a patient who was only the second male in the
literature with all the clinical features of classic CFNS.

Devriendt et al. (1995) reported craniofrontal nasal dysplasia in mother
and son, further illustrating 2 unexplained observations in this
disorder: more severe clinical expression in females and an increased
incidence of miscarriages.

In a review of 41 patients with CFNS studied in Mexico City between 1979
and 1993, Saavedra et al. (1996) reported several unusual manifestations
in females, including thick, wiry, and curly hair (49%), anterior
cranium bifidum (6%), axillary pterygia (9%), unilateral breast
hypoplasia, postpubertal (11%), and asymmetric lower limb shortness
(14%).

Wieland et al. (2002, 2004) reported a 5-generation German family in
which 6 females had features of CFNS, including hypertelorism, orbital
asymmetry, brachycephaly, brachydactyly, and Sprengel deformity
(184400). One affected member, who had 4 miscarriages, had an arcuate
uterus; she also had curly hair, grooved fingernails, and unilateral
breast hypoplasia. One son of an affected female was considered to be
affected because of hypertelorism with an inner canthal distance greater
than the 97th centile at 9 years of age. One male with 2 affected
daughters and no other children was judged to be unaffected or to have
at the most 'microsymptoms.' Wieland et al. (2004) reported 2 more
families with CFNS; additional variable features included agenesis of
the corpus callosum, syndactyly, and scoliosis.

McGaughran et al. (2002) reported a mother and daughter with CFNS; the
daughter also had diaphragmatic hernia. McGaughran et al. (2002) stated
that this was the first reported female case of CFNS associated with
diaphragmatic hernia and suggested that the brothers reported by Morris
et al. (1987) with CFNS and diaphragmatic hernia instead had Teebi
syndrome.

Vasudevan et al. (2006) reported 2 unrelated families in which a mother
and son had CFNS confirmed by molecular analysis. The mothers both had
classic features of CFNS. Both sons had no major craniofacial features
other than telecanthus, but both had congenital diaphragmatic hernia.

Hogue et al. (2010) reported a father and daughter with CFNS and a
truncating mutation in the EFNB1 gene (300035). The father displayed
hypertelorism and a widow's peak, and had pectus carinatum that had been
surgically corrected, whereas the daughter had hypertelorism, bifid
nasal tip, widow's peak, frontal bossing, and a widened metopic suture.
The paternal grandmother did not have hypertelorism, but had a
dysplastic left fifth toe and a reported 'chest deformity' that was not
examined. In addition, the mother had also previously undergone
therapeutic abortion of a female fetus with congenital diaphragmatic
hernia. Hogue et al. (2010) suggested that CFNS should be considered in
patients presenting with congenital diaphragmatic hernia.

INHERITANCE

Rollnick et al. (1981) presented a pedigree most plausibly interpreted
as indicating X-linked inheritance with 'metabolic interference,' a
pattern proposed on theoretic grounds by Johnson (1980). Johnson (1980)
suggested that some disorders may show up only in heterozygotes as a
result of adverse interaction of 2 alleles, neither of which occasions
abnormality when homozygous or hemizygous.

Reynolds et al. (1982) reported a 3-generation family in which 4 females
and 1 male were affected. The mode of inheritance was unclear.

Young and Moore (1984) suggested that CFNS may be lethal in the male.
From a study of 21 unrelated patients with CFNS and their families,
Reich et al. (1985) suggested autosomal dominant inheritance based on 2
instances of apparent male-to-male transmission. An excess of females
(19:2) remained unexplained, but the fact that 10 of 12 sibs of
family-history-positive probands were male appeared to rule against
semilethality in males.

In the family reported by Kumar et al. (1986), the trait may have
occurred in 6 females of 5 generations. Sax and Flannery (1986) reviewed
8 published pedigrees and added a ninth. They concluded that the
segregation does not fit autosomal dominant, autosomal recessive,
X-linked dominant, or X-linked recessive inheritance.

Kere et al. (1990) described variable expression of craniofrontonasal
dysostosis in a 3-generation family. There were 3 severely affected
females, 2 of them daughters of apparently healthy parents. Two male
relatives, including the father of the 2 affected daughters, had orbital
hypertelorism and other minor anomalies. Kere et al. (1990) concluded
that the expression of the gene is modified by the sex of the subject.

In connection with the description of 9 patients with CFNS, Kapusta et
al. (1992) commented on the unusual pattern of familial occurrence:
while affected females apparently transmit the disorder in equal
proportions to sons and daughters, they stated that no male-to-male
transmission had been documented (Grutzner and Gorlin, 1988). Two
affected fathers in their series had an unaffected son. Added to
published information, 8 affected males had reproduced, producing 21
females, all affected, and 8 males, all unaffected.

Of 41 patients with CFNS studied in Mexico City between 1979 and 1993,
Saavedra et al. (1996) found that 35 were female and 6 were male.
Although most cases were sporadic, 7 familial instances were found. They
pointed out that male-to-male transmission had not been observed. They
stated the opinion that CFNS is an 'incompletely understood X-linked
disorder.'

MAPPING

Wieland et al. (2002) described a German family with CFNS in which the
locus appeared to map to the pericentromeric region of the X chromosome,
at Xq12, rather than to Xp22, as had previously been suggested by
Feldman et al. (1997) and Muenke et al. (1997) (see below). Wieland et
al. (2002) showed random X inactivation in affected females, and favored
X-linked inheritance with metabolic interference as the explanation for
the pedigree pattern.

- Possible Genetic Heterogeneity

McPherson et al. (1991) reported a female with typical CFNS manifested
by hypertelorism, slightly bifid nose, turribrachycephaly, sloping
shoulders, minor digital anomalies, short stature, and moderate mental
retardation who also had a terminal deletion of Xpter-p22.2. The
phenotypically normal mother had normal chromosomes. Studying 2
independent cases of CFNS associated with breaks at Xp22, Muenke (1996)
identified YACs that crossed the breakpoints.

By linkage analysis of 12 CFNS families, Feldman et al. (1997) and
Muenke et al. (1997) mapped the disorder to a 13-cM interval on Xp22
(maximum 2-point lod score of 3.9 at theta = 0.0 for DXS8022; and a
multipoint lod score of 5.08 at DXS1224). Detailed phenotypic analysis
in these families showed that females were more severely affected than
males; affected males showed hypertelorism as the only sign, and none
had coronal synostosis in contrast to the findings in their female
relatives. In females, findings included severe hypertelorism with
extremely broad nasal root and severe craniofacial asymmetry, including
orbital asymmetry probably caused by unicoronal synostosis.

MOLECULAR GENETICS

In affected members of 3 unrelated families with CFNS, Wieland et al.
(2004) identified mutations in the EFNB1 gene (300035.0001-300035.0003).

In 24 affected females from 20 unrelated families with CFNS, Twigg et
al. (2004) identified 17 different mutations in the EFNB1 gene (see,
e.g., 300035.0004-300035.0007).

Among 38 unrelated patients with CFNS, Wieland et al. (2005) identified
33 different mutations in the EFNB1 gene, including 26 novel mutations.
Nine cases were familial, and 29 cases were sporadic.

Wieland et al. (2007) identified mutations in the EFNB1 gene in 10 of 13
patients with CFNS. The 3 remaining patients had contiguous gene
deletions involving EFNB1 and the neighboring genes OPHN1 (300127), PJA1
(300420), and EDA (300451).

Wallis et al. (2008) analyzed the EFNB1 gene in 35 unrelated CFNS
patients (16 sporadic cases and 19 familial), and identified mutations
in 19 patients. The authors stated that 33 (20%) of 129 CFNS cases
published to date have no identifiable mutation in the EFNB1 gene and
suggested that those cases might involve misdiagnoses, undetected large
deletions or rearrangements, or mutations outside the EFNB1 coding
region, mosaicism, or additional CFNS loci.

Wieland et al. (2008) showed that cultured fibroblasts derived from
female patients with heterozygous EFNB1 mutations expressed both mutant
and wildtype EFNB1 and that upon clonal expansion it was possible to
separate wildtype and mutant EFNB1-expressing cells in vitro, indicating
that they carry 2 distinct cell populations with respect to EFNB1 gene
function. These results supported cellular interference as being the
cause of the more severe phenotype in CFNS females. Such a situation
does not occur in hemizygous carrier males, who are mildly affected.

*FIELD* SA
Young (1987)
*FIELD* RF
1. Cohen, M. M., Jr.: Craniofrontonasal dysplasia. Birth Defects
Orig. Art. Ser. XV(5B): 85-89, 1979.

2. Devriendt, K.; Van Mol, C.; Fryns, J. P.: Craniofrontonasal dysplasia:
more severe expression in the mother than in her son. Genet. Counsel. 6:
361-364, 1995.

3. Feldman, G. J.; Ward, D. E.; Lajeunie-Renier, E.; Saavedra, D.;
Robin, N. H.; Proud, V.; Robb, L. J.; Der Kaloustian, V.; Carey, J.
C.; Cohen, M. M., Jr.; Cormier, V.; Munnich, A.; Zackai, E. H.; Wilkie,
A. O. M.; Price, R. A.; Muenke, M.: A novel phenotypic pattern in
X-linked inheritance: craniofrontonasal syndrome maps to Xp22. Hum.
Molec. Genet. 6: 1937-1941, 1997.

4. Grutzner, E.; Gorlin, R. J.: Craniofrontonasal dysplasia: phenotypic
expression in females and males and genetic considerations. Oral
Surg. Oral Med. Oral Path. 65: 436-444, 1988.

5. Hogue, J.; Shankar, S.; Perry, H.; Patel, R.; Vargervik, K.; Slavotinek,
A.: A novel EFNB1 mutation (c.712delG) in a family with craniofrontonasal
syndrome and diaphragmatic hernia. Am. J. Med. Genet. 152A: 2574-2577,
2010.

6. Hurst, J.; Baraitser, M.: Craniofrontonasal dysplasia. (Letter) J.
Med. Genet. 25: 133-134, 1988.

7. Johnson, W. G.: Metabolic interference and the + - heterozygote:
a hypothetical form of simple inheritance which is neither dominant
nor recessive. Am. J. Hum. Genet. 32: 374-386, 1980.

8. Kapusta, L.; Brunner, H. G.; Hamel, B. C. J.: Craniofrontonasal
dysplasia. Europ. J. Pediat. 151: 837-841, 1992.

9. Kere, J.; Ritvanen, A.; Marttinen, E.; Kaitila, I.: Craniofrontonasal
dysostosis: variable expression in a three-generation family. Clin.
Genet. 38: 441-446, 1990.

10. Kumar, D.; Clark, J. W.; Blank, C. E.; Patton, M. A.: A family
with craniofrontonasal dysplasia, and fragile site 12q13 segregating
independently. Clin. Genet. 29: 530-537, 1986.

11. McGaughran, J.; Rees, M.; Battin, M.: Craniofrontonasal syndrome
and diaphragmatic hernia. (Letter) Am. J. Med. Genet. 110: 391-392,
2002.

12. McPherson, E.; Estop, A.; Paulus-Thomas, J.: Craniofrontonasal
dysplasia in a girl with del(X)(p22.2). (Abstract) Am. J. Hum. Genet. 49
(suppl.): 150, 1991.

13. Michels, V. V.; Derleth, D. P.; Hoffman, A. D.; Goldston, A. S.
: Craniofrontonasal dysostosis with deafness and axillary pterygia. Am.
J. Med. Genet. 34: 445-450, 1989.

14. Morris, C. A.; Palumbos, J. C.; Carey, J. C.: Delineation of
the male phenotype in craniofrontonasal syndrome. Am. J. Med. Genet. 27:
623-631, 1987.

15. Muenke, M.: Personal Communication. Philadelphia, Penn. 2/25/1996.

16. Muenke, M.; Feldman, G. J.; Ward, D. E.; Lajeunie-Renier, E.;
Saavedra, D.; Robin, N. H.; Proud, V.; Robb, L. J.; Der Kaloustian,
V.; Carey, J. C.; Cohen, M. M., Jr.; Cormier, V.; Munnich, A.; Zackai,
E. H.; Wilkie, A. O. M.; Price, R. A.: A novel phenotypic pattern
in X-linked inheritance: craniofrontonasal syndrome maps to Xp22.
(Abstract) Am. J. Hum. Genet. 61 (suppl.): A49 only, 1997.

17. Pruzansky, S.; Costaras, M.; Rollnick, B. R.: Radiocephalometric
findings in a family with craniofrontonasal dysplasia. Birth Defects
Orig. Art. Ser. XVIII(1): 121-138, 1982.

18. Reich, E. W.; Wishnick, M. M.; McCarthy, J. G.; Risch, N.: Craniofrontal
dysplasia: clinical delineation. (Abstract) Am. J. Hum. Genet. 37:
A72 only, 1985.

19. Reynolds, J. F.; Haas, R. J.; Edgerton, M. T.; Kelly, T. E.:
Craniofrontonasal dysplasia in a three-generation kindred. J. Craniofac.
Genet. Dev. Biol. 2: 233-238, 1982.

20. Rollnick, B.; Day, D.; Tissot, R.; Kaye, C.: A pedigree: possible
evidence for the metabolic interference hypothesis. (Letter) Am.
J. Hum. Genet. 33: 823-826, 1981.

21. Saavedra, D.; Richieri-Costa, A.; Guion-Almeida, M. L.; Cohen,
M. M., Jr.: Craniofrontonasal syndrome: study of 41 patients. Am.
J. Med. Genet. 61: 147-151, 1996.

22. Sax, C. M.; Flannery, D. B.: Craniofrontonasal dysplasia: clinical
and genetic analysis. Clin. Genet. 29: 508-515, 1986.

23. Slover, R.; Sujansky, E.: Frontonasal dysplasia with coronal
craniosynostosis in three sibs. Birth Defects Orig. Art. Ser. XV(5B):
75-83, 1979.

24. Smith, A. C. M.; Manchester, D. K.; McBogg, P.: Craniofrontonasal
dysplasia (CFND): continuing evidence for Johnson's metabolic interference
hypothesis for an X-linked locus. (Abstract) Am. J. Hum. Genet. 45
(suppl.): A65, 1989.

25. Twigg, S. R. F.; Kan, R.; Babbs, C.; Bochukova, E. G.; Robertson,
S. P.; Wall, S. A.; Morriss-Kay, G. M.; Wilkie, A. O. M.: Mutations
of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause
craniofrontonasal syndrome. Proc. Nat. Acad. Sci. 101: 8652-8657,
2004.

26. Vasudevan, P. C.; Twigg, S. R. F.; Mulliken, J. B.; Cook, J. A.;
Quarrell, O. W. J.; Wilkie, A. O. M.: Expanding the phenotype of
craniofrontonasal syndrome: two unrelated boys with EFNB1 mutations
and congenital diaphragmatic hernia. Europ. J. Hum. Genet. 14: 884-887,
2006.

27. Wallis, D.; Lacbawan, F.; Jain, M.; Der Kaloustian, V. M.; Steiner,
C. E.; Moeschler, J. B.; Losken, H. W.; Kaitila, I. I.; Cantrell,
S.; Proud, V. K.; Carey, J. C.; Day, D. W.; and 11 others: Additional
EFNB1 mutations in craniofrontonasal syndrome. Am. J. Med. Genet. 146A:
2008-2012, 2008.

28. Wieland, I.; Jakubiczka, S.; Muschke, P.; Cohen, M.; Thiele, H.;
Gerlach, K. L.; Adams, R. H.; Wieacker, P.: Mutations of the ephrin-B1
gene cause craniofrontonasal syndrome. Am. J. Hum. Genet. 74: 1209-1215,
2004.

29. Wieland, I.; Jakubiczka, S.; Muschke, P.; Wolf, A.; Gerlach, L.;
Krawczak, M.; Wieacker, P.: Mapping of a further locus for X-linked
craniofrontonasal syndrome. Cytogenet. Genome Res. 99: 285-288,
2002.

30. Wieland, I.; Makarov, R.; Reardon, W.; Tinschert, S.; Goldenberg,
A.; Thierry, P.; Wieacker, P.: Dissecting the molecular mechanisms
in craniofrontonasal syndrome: differential mRNA expression of mutant
EFNB1 and the cellular mosaic. Europ. J. Hum. Genet. 16: 184-191,
2008.

31. Wieland, I.; Reardon, W.; Jakubiczka, S.; Franco, B.; Kress, W.;
Vincent-Delorme, C.; Thierry, P.; Edwards, M.; Konig, R.; Rusu, C.;
Schweiger, S.; Thompson, E.; Tinschert, S.; Stewart, F.; Wieacker,
P.: Twenty-six novel EFNB1 mutations in familial and sporadic craniofrontonasal
syndrome (CFNS). Hum. Mutat. 26: 113-118, 2005.

32. Wieland, I.; Weidner, C.; Ciccone, R.; Lapi, E.; McDonald-McGinn,
D.; Kress, W.; Jakubiczka, S.; Collmann, H.; Zuffardi, O.; Zackai,
E.; Wieacker, P.: Contiguous gene deletions involving EFNB1, OPHN1,
PJA1 and EDA in patients with craniofrontonasal syndrome. Clin. Genet. 72:
506-516, 2007.

33. Young, I. D.: Craniofrontonasal dysplasia. J. Med. Genet. 24:
193-196, 1987.

34. Young, I. D.; Moore, J. R.: Craniofrontonasal dysplasia--a distinct
entity with lethality in the male? (Letter) Clin. Genet. 25: 473-475,
1984.

*FIELD* CS
INHERITANCE:
X-linked dominant

GROWTH:
[Height];
Short stature (males)

HEAD AND NECK:
[Head];
Brachycephaly (females);
[Face];
Frontal bossing (females);
Facial asymmetry;
Widow's peak;
[Eyes];
Hypertelorism (males and females);
Telecanthus (females);
Exotropia (females);
Nystagmus (females);
Strabismus (females);
Downslanting palpebral fissures;
[Nose];
Broad nasal root;
Bifid nasal tip;
Hypoplastic nasal tip;
[Mouth];
Cleft lip;
Cleft palate;
[Neck];
Short neck

CHEST:
[External features];
Narrow sloping shoulders;
[Ribs, sternum, clavicles, and scapulae];
Sprengel deformity (females);
Pectus excavatum (males);
Clavicle pseudoarthrosis (males);
[Breasts];
Unilateral breast hypoplasia;
[Diaphragm];
Diaphragmatic hernia

ABDOMEN:
[External features];
Umbilical hernia

GENITOURINARY:
[External genitalia, male];
Hypospadias;
Shawl scrotum

SKELETAL:
[Skull];
Coronal craniosynostosis (females);
Increased interorbital distance (males);
[Limbs];
Asymmetric lower limb shortness;
Joint laxity;
[Hands];
Syndactyly (females);
Brachydactyly (males);
Fifth finger clinodactyly (females);
[Feet];
Syndactyly;
Broad halluces

SKIN, NAILS, HAIR:
[Skin];
Axillary pterygia;
[Nails];
Brittle nails;
Longitudinal splitting;
Grooved nails;
[Hair];
Thick, wiry hair (females);
Widow's peak;
Low posterior hairline

NEUROLOGIC:
[Central nervous system];
Normal intelligence;
Developmental delay;
Hypotonia;
Hypoplastic corpus callosum

MISCELLANEOUS:
Primarily diagnosed in females;
Expression more severe in females than males;
Possible genetic heterogeneity (linkage to Xp22 in some families)

MOLECULAR BASIS:
Caused by mutation in the ephrin B1 gene (EFNB1, 300035.0001)

*FIELD* CN
Marla J. F. O'Neill - updated: 12/30/2011
Cassandra L. Kniffin - updated: 1/26/2010
Kelly A. Przylepa - updated: 6/23/2004
Kelly A. Przylepa - revised: 6/13/2002

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 05/25/2012
joanna: 12/30/2011
ckniffin: 1/26/2010
joanna: 6/23/2004
joanna: 6/13/2002

*FIELD* CN
Marla J. F. O'Neill - updated: 12/16/2010
Cassandra L. Kniffin - updated: 1/26/2010
Marla J. F. O'Neill - updated: 5/5/2009
Cassandra L. Kniffin - updated: 1/10/2008
Cassandra L. Kniffin - reorganized: 10/2/2006
Cassandra L. Kniffin - updated: 9/21/2006
Cassandra L. Kniffin - updated: 8/14/2006
Victor A. McKusick - updated: 7/28/2004
Victor A. McKusick - updated: 5/20/2004
Victor A. McKusick - updated: 10/16/2003
Deborah L. Stone - updated: 10/11/2002
Victor A. McKusick - updated: 1/21/1998
Victor A. McKusick - updated: 10/23/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 12/17/2010
terry: 12/16/2010
wwang: 2/5/2010
ckniffin: 1/26/2010
wwang: 5/29/2009
terry: 5/5/2009
carol: 1/21/2008
ckniffin: 1/10/2008
carol: 10/2/2006
ckniffin: 9/21/2006
wwang: 8/23/2006
ckniffin: 8/14/2006
tkritzer: 7/28/2004
alopez: 5/24/2004
terry: 5/20/2004
terry: 4/9/2004
mgross: 3/17/2004
cwells: 10/16/2003
carol: 10/11/2002
carol: 2/23/1999
mark: 1/25/1998
terry: 1/21/1998
terry: 11/14/1997
terry: 10/28/1997
mark: 10/25/1997
terry: 10/23/1997
mark: 3/3/1996
terry: 2/28/1996
mark: 2/27/1996
terry: 2/20/1996
mimadm: 4/2/1994
carol: 2/17/1993
carol: 1/15/1993
carol: 12/1/1992
supermim: 3/17/1992
supermim: 5/22/1990