Alternative titles; symbols
HGNC Approved Gene Symbol: EVC
SNOMEDCT: 277807007, 62501005; ICD10CM: Q77.6; ICD9CM: 756.55;
Cytogenetic location: 4p16.2 Genomic coordinates (GRCh38): 4:5,711,201-5,829,057 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p16.2 | ?Weyers acrofacial dysostosis | 193530 | Autosomal dominant | 3 |
| Ellis-van Creveld syndrome | 225500 | Autosomal recessive | 3 |
EVC and EVC2 (607261) are single-pass type I transmembrane proteins. They constitutively associate with each other in a ring-like pattern near the ciliary transition zone, a protein barrier between the ciliary and plasma membranes. EVC and EVC2 function by transducing extracellular signals to the nucleus via the hedgehog (see SHH, 600725) signaling pathway (Dorn et al., 2012).
By positional cloning, sequence analysis, and RACE and RT-PCR analysis of human brain cDNA and human fetal kidney RNA, Ruiz-Perez et al. (2000) cloned EVC, which encodes a 992-amino acid protein with a transmembrane domain, 3 nuclear localization signals, and a leucine zipper motif. Northern blot analysis of human adult and fetal tissues detected a 7.0-kb transcript in fetal kidney and lung. In situ hybridization detected low levels of EVC expression in developing bone, heart, kidney, and lung at Carnegie states 19 and 21. In bone, EVC was expressed in the developing vertebral bodies, ribs, and both upper and lower limbs. Expression was higher in the distal limb compared with the proximal limb, an observation that may be related to the limb segments that are most severely affected with the mutant gene. Ruiz-Perez et al. (2000) also detected EVC expression in the branching epithelium and surrounding mesenchyme of the lung, metanephros, and atrial and ventricular myocardium, including both atrial and interventricular septa. Ruiz-Perez et al. (2000) cloned mouse Evc, which shares 66.8% amino acid identity with human EVC.
Ruiz-Perez et al. (2000) determined that the EVC gene contains 24 exons.
Ruiz-Perez et al. (2000) mapped the EVC gene to chromosome 4p16.
Ruiz-Perez et al. (2003) found that the EVC and EVC2 (607261) genes are arranged in a head-to-head configuration with transcription start sites separated by 2,624 bp in the human and 1,647 bp in mouse.
Sund et al. (2009) carried out in situ hybridization and immunofluorescence studies in mouse tissues and whole embryos and found colocalization of Evc and Evc2 mRNA and protein. In developing mouse heart, expression was strongest in the secondary heart field, including both the outflow tract and the dorsal mesenchymal protrusion, but was also found in mesenchymal structures of the atrial septum and the atrioventricular cushions. There was no evidence of direct transcriptional interregulation between the 2 genes. Due to the locus heterogeneity of human mutations predicted to result in a loss of protein function, a bidirectional genomic organization and overlapping expression patterns, Sund et al. (2009) speculated that the EVC and EVC2 proteins may function coordinately in cardiac development and that loss of this coordinate function may result in the characteristics of Ellis-van Creveld syndrome (EVC; 225500).
Caparros-Martin et al. (2013) found that mouse Evc and Evc2 coimmunoprecipitated with Smo (SMOH; 601500) following hedgehog (Hh) activation in cotransfected HEK293 cells. While Smo localized along the entire length of cilia, the 3 proteins colocalized at the base of cilia following Hh activation. Complexes containing C-terminally truncated Evc2 also interacted with Smo, but they were abnormally distributed along the entire length of the cilium in the presence or absence of Hh activation and inhibited Hh signaling.
Using mouse NIH 3T3 cells Pusapati et al. (2014) found that Iqce (617632) coimmunoprecipitated with Efcab7 (617631), Evc, and Evc2. The tetramer was made up of Iqce-Efcab7 and Evc-Evc2 subcomplexes, and the subcomplexes were linked via an Efcab7-Evc2 bridge. In the absence of Iqce and Efcab7, Evc and Evc2 mislocalized from the base of cilia, dispersed throughout the ciliary membrane, and failed to propagate a Hedgehog signal.
Ruiz-Perez et al. (2000) identified a homozygous splice-donor change (604831.0001) in an Amish pedigree with Ellis-van Creveld syndrome, and 6 truncating mutations and a single amino acid deletion in homozygous or compound heterozygous state in 7 additional pedigrees with EVC (see, e.g., 604831.0002-604831.0004). The heterozygous carriers of these mutations did not manifest features of EVC. Ruiz-Perez et al. (2000) identified a heterozygous missense mutation (S307P; 604831.0006) in a man with Weyers acrofacial dysostosis (WAD; 193530), which the authors called Weyers acrodental dysostosis; his daughter had EVC and was compound heterozygous for S307P and a 1-bp deletion (604831.0007)i in the EVC gene inherited from her unaffected mother. Ruiz-Perez et al. (2000) suggested that EVC and WAD are allelic disorders. Ruiz-Perez et al. (2000) also found a heterozygous missense mutation (R443Q; 604831.0005) in a father and his daughter, who both had the heart defect characteristic of EVC and polydactyly, but not short stature; however, Ruiz-Perez and Goodship (2009) reported that the R443Q variant is a rare polymorphism.
Takamine et al. (2004) purported that mutations in the EVC1 gene are not a common finding in Ellis-van Creveld syndrome. They sequenced all 21 coding exons and flanking intron sequences of the EVC1 gene in 10 unrelated cases of EVC and 3 sibs with EVC and found no mutations interpreted as pathologic.
Ruiz-Perez et al. (2007) found that Evc -/- mice were born at the expected mendelian ratio; however, about half of the Evc -/- offspring had died by 2 days after birth. No overt cardiovascular malformations were evident. Surviving Evc -/- mice lived to adulthood, but only when provided with soft, well-hydrated food. They did not breed. Evc -/- mice developed an EVC-like syndrome, including short ribs and limbs and dental abnormalities, but they did not develop polydactyly. Cilia appeared normal in Evc -/- mice, as did Ihh (600726) expression and signaling, Smo-dependent Gli3 (165240) processing, and chondrocyte differentiation. However, expression of Ihh downstream genes Ptch1 (601309) and Gli1 (165220) was markedly reduced in perichondrium and proliferating chondrocytes, concomitant with contraction of the Fgfr3 (134934) expression domain. Chondrocytes appeared to undergo premature hypertrophic differentiation due to decreased Pthrp (168470) expression secondary to defective Hh signaling.
Nakatomi et al. (2013) found that absence of Evc in mice caused various hypo- and hyperplasia defects during molar tooth development. During first molar development in Evc -/- embryos, response to Shh signaling was progressively lost, with the response consistently lost in a buccal-to-lingual direction. Evc -/- embryos also showed displaced activity of the Wnt (see 164820) pathway. Nakatomi et al. (2013) concluded that disrupted activity of the SHH pathway is the primary cause for the variable dental anomalies seen in patients with EVC syndrome and Weyers acrofacial dysostosis.
Consistent with Evc and Evc2 functioning as a complex, Caparros-Martin et al. (2013) found that the skeletal phenotypes of Evc -/- or Evc2 -/- single mutants and Evc -/- Evc2 -/- double mutants were virtually indistinguishable. Smo translocation to the cilium was normal in Evc2 -/- chondrocytes following Hh activation; however, Gli3 recruitment to cilia tips was reduced, and Sufu (607035)/Gli3 dissociation was impaired. Knockdown of Evc via short hairpin RNA in Sufu -/- mouse embryonic fibroblasts reduced mRNA and protein content of Gli1 and Gli2 (165230), suggesting that the Evc/Evc2 complex also promotes Hh signaling downstream of Sufu.
In the Old Order Amish community of Lancaster County, Pennsylvania, in which McKusick et al. (1964) identified 50 cases of Ellis-van Creveld syndrome (EVC; 225500), Ruiz-Perez et al. (2000) identified a G-to-T substitution in intron 13 at position +5. All affected members in 9 branches of the family studied were also homozygous for an arg760-to-gln (R760Q) missense mutation, and both parents of affected individuals and other presumed heterozygotes who carried the splice site mutation were also heterozygous for the R760Q mutation. The R760Q change was presumed to represent a rare polymorphism because it was found in 1 British control and in 1 CEPH control out of 97 normal controls (194 chromosomes) tested. As the EVC gene is not transcribed in lymphocytes, Ruiz-Perez et al. (2000) could not demonstrate that the intronic change led to alternate splicing. However, a change at this position has been reported in association with disease in a number of genes, and alternative splicing has been demonstrated (Krawczak and Cooper, 1997). McKusick (2000) provided perspective on the classic study of dwarfism, including Ellis-van Creveld syndrome, in the Lancaster County Amish. He pointed out that the closely linked presumed polymorphism, R760Q, might be useful in connection with genetic counseling in this group.
In a patient with Ellis-van Creveld syndrome (EVC; 225500), Ruiz-Perez et al. (2000) found homozygosity for a gln879-to-ter (Q879X) mutation in exon 18 of the EVC gene coding sequence.
In a patient with Ellis-van Creveld syndrome (EVC; 225500), Ruiz-Perez et al. (2000) found compound heterozygosity for 2 truncating mutations in the EVC gene: a 1018C-T transition resulting in an arg340-to-ter (R340X) substitution, and a 1-bp deletion (734delT; 604831.0004). The parents were not available for study.
For discussion of the 1-bp deletion in the EVC gene (734delT) that was found in compound heterozygous state in a patient with Ellis-van Creveld syndrome (EVC; 225500) by Ruiz-Perez et al. (2000), see 604831.0003.
This variant, formerly titled ELLIS-VAN CREVELD SYNDROME, has been reclassified based on the report by Ruiz-Perez and Goodship (2009).
Ruiz-Perez et al. (2000) found a heterozygous 1328G-A transition in exon 10 of the EVC gene, resulting in an arg443-to-gln (R443Q) substitution, in a father and daughter with Ellis-van Creveld syndrome (EVC; 225500). Both patients had postaxial polydactyly of hands and feet, partial atrioventricular canal with common atrium, and agenesis of the upper lateral incisors bilaterally with enamel abnormalities. They were not considered to be of short stature (Digilio et al., 1995).
Ruiz-Perez and Goodship (2009) noted that the R443Q variant (rs35953626) has been reported to be a rare polymorphism that is more common in African populations and thus does not account for the phenotype.
In a child with classic Ellis-van Creveld syndrome (EVC; 225500) whose father had short stature, dysplastic nails, and widely spaced conical-shaped teeth without polydactyly (WAD; 193530), previously reported by Spranger and Tariverdian (1995), Ruiz-Perez et al. (2000) found compound heterozygosity for mutations in the EVC gene: a 919T-C transition in exon 7 resulting in a ser307-to-pro (S307P) substitution, which was inherited from the father, and a 1-bp deletion in exon 17, 2456delG (604831.0007), which was inherited from the mother.
D'Asdia et al. (2013) reported a patient (patient 6) with classic EVC who had the S307P mutation and another mutation in the EVC gene; his father was heterozygous for S307P and was clinically unaffected. The authors stated that although S307P is a recurrent mutation in EVC, no other mutation carrier besides the father reported by Ruiz-Perez et al. (2000) had been reported to be affected. D'Asdia et al. (2013) suggested that the clinical outcome of heterozygotes may be influenced by the genetic background of each individual carrier.
For discussion of the 1-bp deletion in the EVC gene (2456delG) that was found in compound heterozygous state in a patient with Ellis-van Creveld syndrome (EVC; 225500) by Ruiz-Perez et al. (2000), see 604831.0006.
Caparros-Martin, J. A., Valencia, M., Reytor, E., Pacheco, M., Fernandez, M., Perez-Aytes, A., Gean, E., Lapunzina, P., Peters, H., Goodship, J. A., Ruiz-Perez, V. L. The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia. Hum. Molec. Genet. 22: 124-139, 2013. [PubMed: 23026747] [Full Text: https://doi.org/10.1093/hmg/dds409]
D'Asdia, M. C., Torrente, I., Consoli, F., Ferese, R., Magliozzi, M., Bernardini, L., Guida, V., Digilio, M. C., Marino, B., Dallapicolla, B., De Luca, A. Novel and recurrent EVC and EVC2 mutations in Ellis-van Creveld syndrome and Weyers acrofacial dysostosis. Europ. J. Med. Genet. 56: 80-87, 2013. [PubMed: 23220543] [Full Text: https://doi.org/10.1016/j.ejmg.2012.11.005]
Digilio, M. C., Marino, B., Giannotti, A., Dallapiccola, B. Single atrium, atrioventricular canal/postaxial hexodactyly indicating Ellis-van Creveld syndrome. Hum. Genet. 96: 251-253, 1995. [PubMed: 7635486] [Full Text: https://doi.org/10.1007/BF00207395]
Dorn, K. V., Hughes, C. E., Rohatgi, R. A smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia. Dev. Cell 23: 823-835, 2012. [PubMed: 22981989] [Full Text: https://doi.org/10.1016/j.devcel.2012.07.004]
Krawczak, M., Cooper, D. N. The human gene mutation database. Trends Genet. 13: 121-122, 1997. [PubMed: 9066272] [Full Text: https://doi.org/10.1016/s0168-9525(97)01068-8]
McKusick, V. A., Egeland, J. A., Eldridge, R., Krusen, D. E. Dwarfism in the Amish. I. The Ellis-van Creveld syndrome. Bull. Johns Hopkins Hosp. 115: 306-336, 1964. [PubMed: 14217223]
McKusick, V. A. Ellis-van Creveld syndrome and the Amish. Nature Genet. 24: 203-204, 2000. [PubMed: 10700162] [Full Text: https://doi.org/10.1038/73389]
Nakatomi, M., Hovorakova, M., Gritli-Linde, A., Blair, H. J., MacArthur, K., Peterka, M., Lesot, H., Peterkova, R., Ruiz-Perez, V. L., Goodship, J. A., Peters, H. Evc regulates a symmetrical response to Shh signaling in molar development. J. Dent. Res. 92: 222-228, 2013. [PubMed: 23315474] [Full Text: https://doi.org/10.1177/0022034512471826]
Pusapati, G. V., Hughes, C. E., Dorn, K. V., Zhang, D., Sugianto, P., Aravind, L., Rohatgi, R. EFCAB7 and IQCE regulate Hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary cilia. Dev. Cell 28: 483-496, 2014. [PubMed: 24582806] [Full Text: https://doi.org/10.1016/j.devcel.2014.01.021]
Ruiz-Perez, V. L., Blair, H. J., Rodriguez-Andres, M. E., Blanco, M. J., Wilson, A., Liu, Y.-N., Miles, C., Peters, H., Goodship, J. A. Evc is a positive mediator of Ihh-regulated bone growth that localises at the base of chondrocyte cilia. Development 134: 2903-2912, 2007. [PubMed: 17660199] [Full Text: https://doi.org/10.1242/dev.007542]
Ruiz-Perez, V. L., Goodship, J. A. Ellis-van Creveld syndrome and Weyers acrodental dysostosis are caused by cilia-mediated diminished response to Hedgehog ligands. Am. J. Med. Genet. 151C: 341-351, 2009. [PubMed: 19876929] [Full Text: https://doi.org/10.1002/ajmg.c.30226]
Ruiz-Perez, V. L., Ide, S. E., Strom, T. M., Lorenz, B., Wilson, D., Woods, K., King, L., Francomano, C., Freisinger, P., Spranger, S., Marino, B., Dallapiccola, B., Wright, M., Meitinger, T., Polymeropoulos, M. H., Goodship, J. Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nature Genet. 24: 283-286, 2000. Note: Erratum: Nature Genet. 25: 125 only, 2000. [PubMed: 10700184] [Full Text: https://doi.org/10.1038/73508]
Ruiz-Perez, V. L., Tompson, S. W. J., Blair, H. J., Espinoza-Valdez, C., Lapunzina, P., Silva, E. O., Hamel, B., Gibbs, J. L., Young, I. D., Wright, M. J., Goodship, J. A. Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome. Am. J. Hum. Genet. 72: 728-732, 2003. [PubMed: 12571802] [Full Text: https://doi.org/10.1086/368063]
Spranger, S., Tariverdian, G. Symptomatic heterozygosity in the Ellis-van-Creveld syndrome? Clin. Genet. 47: 217-220, 1995. [PubMed: 7628126] [Full Text: https://doi.org/10.1111/j.1399-0004.1995.tb03963.x]
Sund, K. L., Roelker, S., Ramachandran, V., Durbin, L., Benson, D. W. Analysis of Ellis van Creveld syndrome gene products: implications for cardiovascular development and disease. Hum. Molec. Genet. 18: 1813-1824, 2009. [PubMed: 19251731] [Full Text: https://doi.org/10.1093/hmg/ddp098]
Takamine, Y., Krejci, P., Mekikian, P. B., Wilcox, W. R. Mutations in the EVC1 gene are not a common finding in the Ellis-van Creveld and short rib-polydactyly type III syndromes. (Letter) Am. J. Med. Genet. 130A: 96-97, 2004. [PubMed: 15368503] [Full Text: https://doi.org/10.1002/ajmg.a.20579]