Widening the mutation spectrum of EVC and EVC2: ectopic expression of Weyer variants in NIH 3T3 fibroblasts disrupts Hedgehog signaling

Hum Mutat. 2009 Dec;30(12):1667-75. doi: 10.1002/humu.21117.

Abstract

Autosomal recessive Ellis-van Creveld syndrome and autosomal dominant Weyer acrodental dysostosis are allelic conditions caused by mutations in EVC or EVC2. We performed a mutation screening study in 36 EvC cases and 3 cases of Weyer acrodental dysostosis, and identified pathogenic changes either in EVC or in EVC2 in all cases. We detected 40 independent EVC/EVC2 mutations of which 29 were novel changes in Ellis-van Creveld cases and 2 were novel mutations identified in Weyer pedigrees. Of interest one EvC patient had a T>G nucleotide substitution in intron 7 of EVC (c.940-150T>G), which creates a new donor splice site and results in the inclusion of a new exon. The T>G substitution is at nucleotide +5 of the novel 5' splice site. The three Weyer mutations occurred in the final exon of EVC2 (exon 22), suggesting that specific residues encoded by this exon are a key part of the protein. Using murine versions of EVC2 exon 22 mutations we demonstrate that the expression of a Weyer variant, but not the expression of a truncated protein that mimics an Ellis-van Creveld syndrome mutation, impairs Hedgehog signal transduction in NIH 3T3 cells in keeping with its dominant effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • DNA Mutational Analysis
  • Dysostoses / complications*
  • Dysostoses / genetics*
  • Ellis-Van Creveld Syndrome / complications
  • Ellis-Van Creveld Syndrome / genetics
  • Female
  • Fibroblasts / metabolism*
  • Hedgehog Proteins / metabolism*
  • Humans
  • Introns / genetics
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Mice
  • Molecular Sequence Data
  • Mutant Proteins / chemistry
  • Mutation / genetics*
  • NIH 3T3 Cells
  • Pedigree
  • Proteins / chemistry
  • Proteins / genetics
  • Signal Transduction*

Substances

  • EVC protein, human
  • EVC2 protein, human
  • EVC2 protein, mouse
  • Evc protein, mouse
  • Hedgehog Proteins
  • Membrane Proteins
  • Mutant Proteins
  • Proteins