title: Deficiency of the cytoskeletal protein SPECC1L leads to oblique facial clefting.
abstract: Genetic mutations responsible for oblique facial clefts (ObFC), a unique class of facial malformations, are largely unknown. We show that loss-of-function mutations in SPECC1L are pathogenic for this human developmental disorder and that SPECC1L is a critical organizer of vertebrate facial morphogenesis. During murine embryogenesis, Specc1l is expressed in cell populations of the developing facial primordial, which proliferate and fuse to form the face. In zebrafish, knockdown of a SPECC1L homolog produces a faceless phenotype with loss of jaw and facial structures, and knockdown in Drosophila phenocopies mutants in the integrin signaling pathway that exhibit cell-migration and -adhesion defects. Furthermore, in mammalian cells, SPECC1L colocalizes with both tubulin and actin, and its deficiency results in defective actin-cytoskeleton reorganization, as well as abnormal cell adhesion and migration. Collectively, these data demonstrate that SPECC1L functions in actin-cytoskeleton reorganization and is required for proper facial morphogenesis.
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. maas@genetics.med.harvard.edu
authors.forename: Irfan
authors.initials: I
authors.lastname: Saadi
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Gisselbrecht
authors.forename: Wolfram
authors.initials: W
authors.lastname: Goessling
authors.forename: Resy
authors.initials: R
authors.lastname: Cavallesco
authors.forename: Annick
authors.initials: A
authors.lastname: Turbe-Doan
authors.forename: Aline L
authors.initials: AL
authors.lastname: Petrin
authors.forename: James
authors.initials: J
authors.lastname: Harris
authors.forename: Ursela
authors.initials: U
authors.lastname: Siddiqui
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Grix
authors.forename: Hanne D
authors.initials: HD
authors.lastname: Hove
authors.forename: Philippe
authors.initials: P
authors.lastname: Leboulch
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Glover
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Morton
authors.forename: Antonio
authors.initials: A
authors.lastname: Richieri-Costa
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.forename: Robert P
authors.initials: RP
authors.lastname: Erickson
authors.forename: Richard L
authors.initials: RL
authors.lastname: Maas
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002972:Cleft Palate / Q000235:genetics* / Q000473:pathology; D003394:Craniofacial Dysostosis / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000172:deficiency*; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D005124:Eye Abnormalities / Q000235:genetics* / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D019767:Maxillofacial Abnormalities / Q000235:genetics* / Q000473:pathology; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014404:Tubulin / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D000096985:Calponins
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; D010750:Phosphoproteins; D014404:Tubulin; D051153:Wnt Proteins; C558855:SPECC1L protein, human; D000096985:Calponins