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ALX4 gain-of-function mutations in non-syndromic craniosynostosis

  • Author(s): Yagnik, Garima;
  • Ghuman, Apar;
  • Kim, Sundon;
  • Stevens, Cristina G.;
  • Kimonis, Virginia;
  • Stoler, Joan;
  • Sanchez-Lara, Pedro;
  • Bernstein, Jonathan;
  • Naydenov, Cyril;
  • Drissi, Hicham;
  • Cunningham, Michael L.;
  • Kim, Jinoh;
  • Boyadjiev, Simeon A.
  • et al.
Abstract

Craniosynostosis is the early fusion of one or more sutures of the infant skull and is a common defect occurring in approximately 1 of every 2,500 live births. Non-syndromic craniosynostosis accounts for approximately 80% of all cases and is thought to have strong genetic determinants that are yet to be identified. ALX4 is a homeodomain transcription factor with known involvement in osteoblast regulation. By direct sequencing of the ALX4 coding region in sagittal or sagittal-suture-involved non-syndromic craniosynostosis probands, we identified novel, nonsynonymous, familial variants in three of 203 individuals with NSC. Using dual-luciferase assay we show that two of these variants (V7F and K211E) confer a significant gain-of-function effect on ALX4. Our results suggest that ALX4 variants may have an impact on the genetic etiology of NSC.

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