Deficiency of the cytoskeletal protein SPECC1L leads to oblique facial clefting

Am J Hum Genet. 2011 Jul 15;89(1):44-55. doi: 10.1016/j.ajhg.2011.05.023. Epub 2011 Jun 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Actins
  • Cytoskeletal Proteins
  • Mip1 phosphoprotein, human
  • Phosphoproteins
  • Tubulin
  • Wnt Proteins

Supplementary concepts

  • Oculomaxillofacial dysostosis