title: 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.affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid and CIBER de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Valencia
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.forename: Derek
authors.initials: D
authors.lastname: Lim
authors.forename: Raffaella
authors.initials: R
authors.lastname: Zannolli
authors.forename: Deborah
authors.initials: D
authors.lastname: Bartholdi
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.forename: Othman
authors.initials: O
authors.lastname: Al-Ajlouni
authors.forename: Suhair S
authors.initials: SS
authors.lastname: Eid
authors.forename: Helen
authors.initials: H
authors.lastname: Cox
authors.forename: Sabrina
authors.initials: S
authors.lastname: Buoni
authors.forename: Joseph
authors.initials: J
authors.lastname: Hayek
authors.forename: Maria L
authors.initials: ML
authors.lastname: Martinez-Frias
authors.forename: Perez-Aytes
authors.initials: PA
authors.lastname: Antonio
authors.forename: Samia
authors.initials: S
authors.lastname: Temtamy
authors.forename: Mona
authors.initials: M
authors.lastname: Aglan
authors.forename: Judith A
authors.initials: JA
authors.lastname: Goodship
authors.forename: Victor L
authors.initials: VL
authors.lastname: Ruiz-Perez
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004413:Dysostoses / Q000150:complications* / Q000235:genetics*; D004613:Ellis-Van Creveld Syndrome / Q000150:complications / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007438:Introns / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry; D009154:Mutation / Q000235:genetics*; D041681:NIH 3T3 Cells; D010375:Pedigree; D011506:Proteins / Q000737:chemistry / Q000235:genetics; D015398:Signal Transduction
chemical_list: C406058:EVC protein, human; C473310:EVC2 protein, human; C541939:EVC2 protein, mouse; C523527:Evc protein, mouse; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D050505:Mutant Proteins; D011506:Proteins