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

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.

• Authors: 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
• Journal: Human mutation (Hum Mutat) Vol. 30 Issue 12 Pg. 1667-75 (Dec 2009) ISSN: 1098-1004 [Electronic] United States
• PMID: 19810119 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• EVC protein, human
• EVC2 protein, human
• EVC2 protein, mouse
• Evc protein, mouse
• Hedgehog Proteins
• Intercellular Signaling Peptides and Proteins
• Membrane Proteins
• Mutant Proteins
• Proteins

Topics

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