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Deficiency of the cytoskeletal protein SPECC1L leads to oblique facial clefting

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  • Irfan Saadi
  • Fowzan S Alkuraya
  • Stephen S Gisselbrecht
  • Wolfram Goessling
  • Resy Cavallesco
  • Annick Turbe-Doan
  • Aline L Petrin
  • James Harris
  • Ursela Siddiqui
  • Arthur W Grix
  • Hanne Buciek Hove
  • Philippe Leboulch
  • Thomas W Glover
  • Cynthia C Morton
  • Antonio Richieri-Costa
  • Jeffrey C Murray
  • Robert P Erickson
  • Richard L Maas
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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.
Original languageEnglish
JournalAmerican Journal of Human Genetics
Volume89
Issue number1
Pages (from-to)44-55
Number of pages12
ISSN0002-9297
DOIs
Publication statusPublished - 2011

    Research areas

  • Actins, Animals, Cell Adhesion, Cell Line, Cell Movement, Cell Proliferation, Cleft Palate, Craniofacial Dysostosis, Cytoskeletal Proteins, Drosophila, Eye Abnormalities, Female, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Humans, In Situ Hybridization, Male, Maxillofacial Abnormalities, Microtubules, Mutation, Phenotype, Phosphoproteins, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Tubulin, Wnt Proteins, Zebrafish

ID: 33282920