Widening the mutation spectrum of EVC and EVC2: ectopic expression of Weyer variants in NIH 3T3 fibroblasts disrupts hedgehog signaling
✍ Scribed by Maria Valencia; Pablo Lapunzina; Derek Lim; Raffaella Zannolli; Deborah Bartholdi; Bernd Wollnik; Othman Al-Ajlouni; Suhair S. Eid; Helen Cox; Sabrina Buoni; Joseph Hayek; Maria L. Martinez-Frias; Perez-Aytes Antonio; Samia Temtamy; Mona Aglan; Judith A. Goodship; Victor L. Ruiz-Perez
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 375 KB
- Volume
- 30
- Category
- Article
- ISSN
- 1059-7794
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✦ Synopsis
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 T4G nucleotide substitution in intron 7 of EVC (c.940À150T4G), which creates a new donor splice site and results in the inclusion of a new exon. The T4G substitution is at nucleotide 15 of the novel 5 0 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.