Alternative titles; symbols
HGNC Approved Gene Symbol: EVC2
SNOMEDCT: 277807007, 62501005; ICD10CM: Q77.6; ICD9CM: 756.55;
Cytogenetic location: 4p16.2 Genomic coordinates (GRCh38) : 4:5,529,011-5,709,548 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p16.2 | Ellis-van Creveld syndrome | 225500 | Autosomal recessive | 3 |
| Weyers acrofacial dysostosis | 193530 | Autosomal dominant | 3 |
EVC (604831) and EVC2 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).
Takeda et al. (2002) identified a bovine gene, which they called limbin (Lbn), that is expressed in the epiphyseal growth plates of long bone. By cDNA cloning, RT-PCR, and RACE, Takeda et al. (2002) isolated the human and mouse LBN genes. The predicted 1,228-amino acid human protein and the 1,220-amino acid mouse protein share 79% and 68% homology with the bovine lbn protein, respectively. A putative transmembrane domain, 2 coiled-coil domains, and 3 nuclear localization signals are conserved between the human, mouse, and bovine proteins. Northern blot analysis of mouse tissues detected a 4.5-kb transcript in long bone, cranial bone, kidney, and heart, and expression was detected in embryos at days 7, 11, 15, and 17. In situ hybridization revealed strong expression of Lbn in limb buds of developing mouse embryos and in proliferating chondrocytes and bone-forming osteoblasts in long bones. Takeda et al. (2002) concluded that LBN has an essential role in skeletal development.
Galdzicka et al. (2002) independently cloned the EVC2 gene and found that the transcription start sites of EVC and EVC2 are separated by only 1,643 basepairs. Northern blot analysis of EVC2 showed a single major band of 4.8 kb in heart, placenta, lung, liver, skeletal muscle, kidney, and pancreas. A transcript of 4.8 kb was also found by RT-PCR in lymphoblasts and chondrocytes.
Galdzicka et al. (2002) determined that the EVC2 gene contains of 23 exons. There are at least 3 alternate transcription start sites, and exon 1 is not translated, with the first ATG of the open reading frame occurring in exon 2. There are 2 transcripts with alternative 3-prime ends, one including exon 22A and the other including exons 22B and 23B. Exons 16 and 18 are also subject to alternative splicing and have tissue-specific shorter and longer versions.
By genomic sequence analysis, Takeda et al. (2002) mapped the EVC2 gene to chromosome 4p16.
Ruiz-Perez et al. (2003) found that the EVC and EVC2 genes are arranged in a divergent configuration with transcription start sites separated by 2,624 bp in the human and 1,647 bp in mouse. Adachi and Lieber (2002) had concluded that such head-to-head configurations may be a common feature of the human genome. Shimada et al. (1989) and Platzer et al. (1997) gave examples of coregulation by a single promoter with bidirectional activity.
Ruiz-Perez et al. (2003) found no obvious similarities between EVC and EVC2, and, other than the predicted transmembrane domains, there were no motifs giving clues to their function. Ruiz-Perez et al. (2003) pointed out that EVC and EVC2 lie within a syntenic region with conserved gene order and transcription orientation encompassing NSG1 (607645), STX18 (606046), MSX1 (142983), and C17. The gene encoding collapsin response mediator protein-1 (CRMP1; 602462) lies immediately adjacent to the EVC gene on the opposite side of EVC2 where its 3-prime end overlaps with the 3-prime end of EVC, i.e., in tail-to-tail orientation.
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 these proteins may function coordinately in cardiac development and that loss of this coordinate function may result in the characteristics of Ellis-van Creveld syndrome (225500).
Using mouse fibroblasts, Dorn et al. (2012) found that knockdown of Evc2 did not affect cilia formation but inhibited activated Shh induction of Gli1 (165220), which is a direct hedgehog (Hh) target. Knockdown of Evc2 also blocked Hh-induced differentiation of mouse mesenchymal cells into osteoblasts. C-terminal truncation of Evc2 or mutation of a phe-val (FV) motif near the C terminus abrogated targeting of Evc2 to the base of cilia, caused redistribution of Evc2 along the entire length of the ciliary membrane, and functioned as a dominant-negative inhibitor of Hh signaling. Upon Hh activation, Evc2 and Evc also transiently interacted with activated Smo (SMOH; 601500), a transducer of Hh signaling. Knockdown of Evc2 blunted Smo-dependent recruitment of downstream Sufu (607035) and Gli proteins to the tips of primary cilia. Dorn et al. (2012) concluded that EVC proteins are transducers of Hh signals and further hypothesized that mutations in these proteins that are associated with EVC syndrome are nonfunctional because they fail to localize to cilia. In contrast, truncating mutations linked to Weyers acrofacial dysostosis (193530) interfere in a dominant-negative manner with Hh signaling because truncated proteins mislocalize throughout the ciliary membrane.
Independently, Caparros-Martin et al. (2013) found that mouse Evc and Evc2 coimmunoprecipitated with Smo following Hh activation in transfected HEK293 cells. 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.
In a patient with Ellis-van Creveld syndrome of Ashkenazi Jewish origin, Galdzicka et al. (2002) identified 2 homozygous mutations in the EVC2 gene; see 607261.0007.
Ruiz-Perez et al. (2003) identified an individual with Ellis-van Creveld syndrome in a consanguineous Gypsy pedigree who had a shorter region of homozygosity, excluding MSX1, and did not have an EVC mutation. Examination of the human and mouse databases showed several genes of particular interest in the narrowed critical region identified by study of the Gypsy family. Of particular interest among the genes in the critical region was EVC2, mutated in its bovine homolog in bovine chondrodysplastic dwarfism (Takeda et al., 2002). Ruiz-Perez et al. (2003) performed 5-prime RACE in adult human kidney RNA, using gene-specific primers. The RACE product, confirmed by RT-PCR, showed an additional GC-rich exon containing an in-frame AUG with loss of the open reading frame 21 nucleotides upstream. This additional sequence had homology to the N-terminus of the murine ortholog. Ruiz-Perez et al. (2003) aligned the extended cDNA against the human genome sequence to design primers to amplify the 22 coding exons in 7 consanguineous probands. They found 5 truncating mutations and a missense change in the EVC2 gene. In the seventh consanguineous pedigree, they identified no mutation.
Ye et al. (2006) identified a heterozygous 1-bp deletion in exon 22 of the EVC2 gene (3793delC; 607261.0009) in affected members of a Chinese family with autosomal dominant Weyers acrofacial dysostosis (WAD; 193530) spanning 5 generations. The findings confirmed that the disorder is allelic to Ellis-van Creveld syndrome.
In a 6-year-old Chinese girl with mild Ellis-van Creveld syndrome, Shen et al. (2011) identified compound heterozygosity for a splice site and a missense mutation in the EVC2 gene (607261.0010-607261.0011). The authors noted that all 3 Weyers acrofacial dysostosis-associated mutations reported to date were located in exon 22 of EVC2, whereas this patient's mutations were in IVS5 and exon 15.
Valencia et al. (2009) performed direct analysis of the EVC and EVC2 genes in 3 patients with Weyers acrofacial dysostosis and identified a heterozygous mutation in the EVC2 gene in all: the previously identified 3793delC mutation, and 2 novel mutations that occurred at the same nucleotide position, 3797T-G (607261.0012) and 3797T-A (607261.0013), both of which resulted in truncation of the protein at leu1266. All 3 mutations were tightly clustered at the 3-prime end of exon 22, indicating a mutation hotspot for this disorder. In vitro studies in NIH 3T3 cells showed that the Hedgehog signaling pathway is impaired in cells mimicking WAD mutations but is fully active in cells mimicking EVC syndrome mutations. This finding was in keeping with the manifestation of an affected phenotype in individuals heterozygous for WAD-related mutations but not in individuals heterozygous for EVC syndrome-related mutations.
In 2 patients with WAD, D'Asdia et al. (2013) also identified heterozygous mutations in exon 22 of the EVC2 gene: the previously identified 3793delC mutation and a novel nonsense mutation (G1269X; 607261.0012).
Chondrodysplastic dwarfism in Japanese brown cattle is an autosomal recessive disorder characterized by short limbs, joint abnormalities, and ateliosis (Moritomo et al., 1992). Long bones of the affected animals have insufficient endochondral ossification with irregularly arranged chondrocytes, abnormal formation of the cartilaginous matrix, and partial disappearance of the epiphyseal growth plates. The axial skeletal structures and craniofacial skeleton are not significantly affected. Yoneda et al. (1999) mapped the Bcd gene to the distal end of bovine chromosome 6 in a region that shows homology of synteny to human chromosome 4p. They noted that several human chondrodystrophies, including the most frequent form, achondroplasia (100800), are localized to this region. However, in all of these disorders, the phenotype differs from that of Bcd. Takeda et al. (2002) narrowed the Bcd locus to a 2.4-cM region, constructed YAC and BAC contigs covering this region, and identified a gene, which they called limbin (Lbn), that is expressed in the epiphyseal growth plates of long bone. They identified causative mutations in the Lbn gene in calves affected with BCD. One mutation was a 1-bp substitution leading to inactivation of a cryptic splice donor site, and the other was a 1-bp deletion resulting in a frameshift.
Murgiano et al. (2014) determined that chondrodysplastic dwarfism in Tyrolean grey cattle, also known as Grauvich or Alpine grey cattle, is an autosomal recessive disorder caused by a loss-of-function mutation in the EVC2 gene on chromosome 6. All affected calves were bright and alert but had difficulty rising and/or maintaining a quadrupedal stance and had a wobbling gait. The limbs were disproportionately short and bulky, variably rotated, and arched in a dumbbell-like position. The calves had moderate to severe joint laxity. The splanchnocranium, mandible, and palate were normal, as was the heart, and there was no polydactyly. The bones were not osteopenic and there were no fractures. The femur and humerus were the most severely shortened. Histopathologic examination of 2 affected calves revealed that the growth plate of long bones and vertebrae, which were grossly normal, was irregular. Affected female calves had abnormal genitalia, defined as precocious growth.
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 (165240) recruitment to cilia tips was reduced and Sufu/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 a consanguineous Gypsy pedigree, Ruiz-Perez et al. (2003) found that members with Ellis-van Creveld syndrome (225500) had a frameshift mutation (3660delC) in exon 22 of the gene they characterized and designated EVC2. The clinical features in affected individuals in this family included atrioventricular septal defects, mesomelic limb shortening with genu valgum, polydactyly with nail dysplasia, multiple oral frenula, and dysplastic teeth. Two affected individuals in earlier generations were said to have postaxial polydactyly and congenital heart defects but no other features of EVC.
In the Brazilian kindred originally reported by da Silva et al. (1980), Ruiz-Perez et al. (2003) found that individuals with Ellis-van Creveld syndrome (225500) had a 5-bp insertion in exon 1, 198insGGCGG. Clinical features in this family included atrial septal defect, short limb dysplasia with genu valgum, polydactyly, multiple oral frenula, oligodontia, and dysplastic teeth.
In a child with Ellis-van Creveld syndrome (225500) of second-cousin parents, who presented with short limb dysplasia, short ribs, postaxial polydactyly of the hands, dysplastic nails and teeth, and hyperplasia of the alveolar ridges and multiple oral frenula, as well as patent ductus arteriosus, Ruiz-Perez et al. (2003) detected a frameshift (2056insC) in exon 14 of the EVC2 gene.
In a stillborn child with Ellis-van Creveld syndrome (225500) who had ventricular septal defect and short limbs with postaxial polydactyly of the hands and radiographic features typical of EVC, with short limbs and classic pelvic configuration, Ruiz-Perez et al. (2003) found an 1195C-T transition in exon 10 of the EVC2 gene that introduced a nonsense codon (arg399 to stop).
In an Ecuadorian family in which 2 daughters had Ellis-van Creveld syndrome (225500) , Ruiz-Perez et al. (2003) found an 1855C-T transition in exon 12 of the EVC2 gene creating a nonsense codon (gln619 to stop). Both had disproportionate short stature with acromesomelic limb shortening and short ribs. In the hands, there was postaxial polydactyly with nail dysplasia and fusion of the hamate and capitate. Both had oligodontia with dysplastic teeth and multiple oral frenula. One of the girls had genu valgum.
In a family with 2 sibs with Ellis-van Creveld syndrome (225500), Ruiz-Perez et al. (2003) found a missense mutation, ile283 to arg (I283R), in exon 7 of the EVC2 gene that was not present in 100 control chromosomes. Both affected sibs had ostium primum atrial septal defects with short limb dysplasia, postaxial polydactyly of the hands, and nail and tooth dysplasia.
In a boy with Ellis-van Creveld syndrome (225500), who was born to Ashkenazi Jewish parents, Galdzicka et al. (2002) identified homozygosity for 2 mutations in the EVC2 gene: a 3754C-T transition in exon 18 resulting in a gln1009-to-ter (Q1009X) substitution, and a 3337C-T transition in exon 17 resulting in an arg870-to-trp (R870W; 607261.0008) substitution. The parents were heterozygous for both mutations. Neither mutation was identified in a panel of 319 control Ashkenazi DNAs.
For discussion of the arg870-to-trp (R870W) mutation in the EVC2 gene that was found in homozygosity with another homozygous EVC2 mutation in a family segregating Ellis-van Creveld syndrome (225500) by Galdzicka et al. (2002), see 607261.0007.
In affected members of a Chinese family with autosomal dominant Weyers acrofacial dysostosis (193530), Ye et al. (2006) identified a heterozygous 1-bp deletion (3793delC) in exon 22 of the EVC2 gene, resulting in a frameshift and premature stop at codon 1266. The mutation was not identified in 300 control chromosomes.
In affected members of a family segregating Weyers acrofacial dysostosis, Valencia et al. (2009) identified heterozygosity for the 3793delC mutation.
D'Asdia et al. (2013) identified the same heterozygous mutation in another patient with Weyers acrofacial dysostosis.
In a 6-year-old Chinese girl with mild Ellis-van Creveld syndrome (225500), Shen et al. (2011) identified compound heterozygosity for an A-G transition in intron 5 (IVS5-2A-G) of the EVC2 gene, predicted to cause exon skipping and result in a truncated protein, and a 2653C-T transition in exon 15, resulting in an arg884-to-ter (R884X; 607261.0011) substitution. The unaffected parents were each heterozygous for 1 of the mutations, respectively; neither mutation was found in 200 control chromosomes.
For discussion of the arg884-to-ter (R884X) mutation in the EVC2 gene that was found in compound heterozygous state in a patient with mild Ellis-van Creveld syndrome (225500) by Shen et al. (2011), see 607261.0010.
In affected members of a family segregating Weyers acrofacial dysostosis (193530), previously reported by Zannolli et al. (2008), Valencia et al. (2009) identified a heterozygous 3797T-G transversion in exon 22 of the EVC2 gene, which resulted in truncation of the protein at Leu1266. Two affected members of the family also had mental retardation.
In a patient with Weyers acrofacial dysostosis (193530), Valencia et al. (2009) identified a heterozygous 3797T-A transversion in exon 22 of the EVC2 gene, which resulted in truncation of the protein at Leu1266.
In a patient with Weyers acrofacial dysostosis (193530), D'Asdia et al. (2013) identified a heterozygous 3805G-T transversion in exon 22 of the EVC2 gene, resulting in a gly1269-to-ter (G1269X) substitution.
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