ALX4 gain-of-function mutations in nonsyndromic craniosynostosis

Hum Mutat. 2012 Dec;33(12):1626-9. doi: 10.1002/humu.22166. Epub 2012 Aug 13.

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. Nonsyndromic craniosynostosis (NSC) 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 nonsyndromic 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.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Conserved Sequence
  • Craniosynostoses / genetics*
  • DNA-Binding Proteins / genetics*
  • Gene Frequency
  • Genetic Association Studies
  • Humans
  • Mutation, Missense*
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, DNA
  • Transcription Factors / genetics*

Substances

  • ALX4 protein, human
  • DNA-Binding Proteins
  • Transcription Factors