Alternative titles; symbols
HGNC Approved Gene Symbol: NECTIN4
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38): 1:161,070,998-161,089,558 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.3 | Ectodermal dysplasia-syndactyly syndrome 1 | 613573 | Autosomal recessive | 3 |
Nectin-4, or PVRL4, belongs to the nectin subfamily of immunoglobulin-like adhesion molecules that participate in Ca(2+)-independent cell-cell adhesion. Nectins bind to the actin cytoskeleton through the adaptor protein afadin (AFDN; 159559) and are key components of adherens junctions (summary by Barron et al. (2008)).
By database analysis, Reymond et al. (2001) identified the PVRL4 gene, which encodes a 510-amino acid protein with a predicted molecular mass of 55.5 kD. It contains 1 predicted transmembrane domain, followed by a 139-residue cytoplasmic sequence. Human and murine PVRL4 share 92% amino acid identity. Northern blot analysis showed strong expression of a 3.7-kb human PVRL4 transcript in placenta and weak expression in trachea. Murine Pvrl4 was expressed at embryonic days 11, 15 and 17. Immunohistochemistry revealed that human PVRL4 localizes to endothelial cells from vessels in placental villi.
Brancati et al. (2010) found expression of PVRL4 in human skin, hair follicles, and cultured keratinocytes, but not in fibroblasts. Immunohistochemical studies of skin detected expression of nectin-4 at cell-cell junctions of keratinocytes, with particular staining in all the suprabasal nucleated layers of epidermis, and in all the nonkeratinized structures of hair. In the mouse, there was interdigital Pvrl4 expression at embryonic stage E15.5.
Reymond et al. (2001) determined that the PVRL4 gene contains 9 exons.
Hartz (2010) mapped the PVRL4 gene to chromosome 1q23.3 based on an alignment of the PVRL4 sequence (GenBank AF160477) with the genomic sequence (GRCh37).
Using immunoprecipitation and yeast 2-hybrid analyses, Reymond et al. (2001) showed that the C-terminal cytoplasmic region of PVRL4 interacted with the PDZ domain of the F-actin-associated protein afadin (MLLT4; 159559). The 2 proteins colocalized at intercellular adherens junctions in epithelial cells. Reymond et al. (2001) observed PVRL4 interaction with itself and binding to the V domain of PVRL1, but not to other PVRLs.
Fabre-Lafay et al. (2005) reported that PVRL4 was expressed in breast cancers and a circulating form of PVRL4 was present in sera from metastatic breast cancer patients. Using epitope mapping and immunoprecipitation, the authors showed that soluble forms of PVRL4 in both breast tumor cell lines and breast cancer patients had similar biochemical and immunologic features. PVRL4 was cleaved by the metalloproteinase ADAM17 (603639) in breast tumor cell lines and PVRL4-transfected Chinese hamster ovary cells.
Measles virus initially infects airway macrophages and dendritic cells using SLAMF1 (603492) as receptor. These cells then cross the respiratory epithelium and transport the infection to lymphatic organs, where the virus replicates vigorously before crossing back into the airways. Using flow cytometric, small interfering RNA, and fluorescent microscopy analyses on measles virus-permissive epithelial cell lines, Muhlebach et al. (2011) identified nectin-4 as a candidate host exit receptor. Nectin-4 interacted with the viral attachment protein with high affinity through its membrane-distal domain. Nectin-4 sustained measles virus entry and noncytopathic spread in differentiated human epithelial airway sheets infected basolaterally. Confocal microscopy demonstrated downregulation of Nectin-4 in infected epithelial cells, including those of macaque trachea. Muhlebach et al. (2011) noted high expression of Nectin-4 in numerous cancers and the oncolytic effects of measles virus on cancer cells and proposed that measles virus-based trials be extended from ovarian to breast and lung cancer.
In affected members of a consanguineous Algerian family segregating ectodermal dysplasia-syndactyly syndrome-1 (EDSS1; 613573), originally described by Boudghene-Stambouli and Merad-Boudia (1991), Brancati et al. (2010) identified a homozygous mutation in the PVRL4 gene (609607.0001). In affected members of a nonconsanguineous Italian family with EDSS1, they identified compound heterozygosity for mutations in the PVRL4 gene (609607.0002-609607.0003). There was decreased PVRL4 immunostaining in the interfollicular epidermis and hair follicles of 1 patient. There was also highly disorganized cell membrane staining of alpha-catenin (CTNNA1; 116805), beta-catenin (CTNNB1; 116806), E-cadherin (CDH1; 192090), and afadin (MLLT4; 159559) in patient skin.
In affected members of a consanguineous Pakistani family with EDSS1, Jelani et al. (2011) identified a homozygous mutation in the PVRL4 gene (P212R; 609607.0004). The mutation was found after homozygosity mapping identified linkage to chromosome 1q23. The findings implicated a role of cell adhesion molecules in the pathogenesis of the disorder.
In 3 sibs with EDSS, whose parents were first cousins once removed, Fortugno et al. (2014) identified homozygosity for a missense mutation (V242M; 613573.0005) in the PVRL4 gene. The unaffected parents were heterozygous for the mutation.
In affected members of a large 5-generation consanguineous Pakistani family with EDSS, Raza et al. (2015) identified homozygosity for a nonsense mutation in the PVRL4 gene (Q61X; 609607.0006) that segregated with disease and was not found in controls.
In affected members of a consanguineous Algerian family segregating ectodermal dysplasia-syndactyly syndrome-1 (EDSS1; 613573), originally described by Boudghene-Stambouli and Merad-Boudia (1991), Brancati et al. (2010) identified homozygosity for an 8516G-A transition in exon 4 of the PVRL4 gene, resulting in an arg284-to-gln (R284Q) substitution and exon skipping. This mutation was transmitted from heterozygous parents to all 4 homozygous patients, and carrier status was demonstrated in 3 healthy sibs according to haplotype reconstruction. The mutation was not found in 250 DNA samples from various geographic regions (including 70 Algerian samples) and was not listed as a SNP in public databases.
In affected members of a nonconsanguineous Italian family segregating ectodermal dysplasia-syndactyly syndrome-1 (EDSS1; 613573), Brancati et al. (2010) identified compound heterozygosity for 2 mutations in the PVRL4 gene: a maternally inherited 554C-T transition in exon 3, resulting in a thr185-to-met (T185M) substitution, and a paternally inherited single base deletion (906delT; 609607.0003) in exon 5, resulting in a frameshift with premature termination (pro304hisfsTer2). Both mutations were absent in a panel of 180 ethnically matched control DNA samples.
Fortugno et al. (2014) performed functional analysis of the T185M mutation using patient skin and primary keratinocytes as well as ectopic expression of PVRL4 in epithelial cell lines. They observed perturbed clustering of nectin-1 (NECTIN1; 600644) at keratinocyte contact sites with the T185M mutant compared to wildtype PVRL4; in addition, there was delayed cell-cell aggregation and cadherin (see 192090) recruitment at adherens junctions.
For discussion of the 1-bp deletion (906delT) in the PVRL4 gene that was found in compound heterozygous state in patients with ectodermal dysplasia-syndactyly syndrome-1 (EDSS1; 613573) by Brancati et al. (2010), see 609607.0002.
In affected members of a consanguineous Pakistani family with ectodermal dysplasia-syndactyly syndrome-1 (EDSS1; 613573), Jelani et al. (2011) identified a homozygous 635C-G transversion in exon 3 of the PVRL4 gene, resulting in a pro212-to-arg (P212R) substitution in a highly conserved residue in the second Ig-like (C2-type 1) domain. The mutation, which was not found in 200 controls, is predicted to disrupt the structure of the protein. All patients had sparse scalp hair, sparse to absent eyebrows and eyelashes, conical and cylindrical teeth with enamel hypoplasia, hypoplastic nails, and cutaneous syndactyly of the third and fourth fingers and second and third toes. Most also had hyperkeratosis of the palms. None had hypo- or hyperhidrosis, cognitive impairment, or other systemic involvement.
In 3 sibs with ectodermal dysplasia-syndactyly syndrome (EDSS1; 613573), whose parents were first cousins once removed, Fortugno et al. (2014) identified homozygosity for a c.724G-A transition in exon 3 of the PVRL4 gene, resulting in a val242-to-met (V242M) substitution. The unaffected parents were heterozygous for the mutation. Fortugno et al. (2014) performed functional analysis of the mutation using patient skin and primary keratinocytes as well as ectopic expression of PVRL4 in epithelial cell lines. They observed perturbed clustering of nectin-1 (NECTIN1; 600644) at keratinocyte contact sites with the T185M mutant compared to wildtype PVRL4; in addition, there was delayed cell-cell aggregation and cadherin (see 192090) recruitment at adherens junctions.
In 3 affected members, including 2 sibs, from a large 5-generation consanguineous Pakistani family with ectodermal dysplasia and syndactyly (EDSS1; 613573), Raza et al. (2015) identified homozygosity for a c.181C-T transition in exon 2 of the PVRL4 gene, resulting in a gln61-to-ter (Q61X) substitution. The unaffected parents and 2 unaffected sibs were heterozygous for the mutation, which was not found in 100 ethnically matched controls.
Barron, M. J., Brookes, S. J., Draper, C. E., Garrod, D., Kirkham, J., Shore, R. C., Dixon, M. J. The cell adhesion molecule nectin-1 is critical for normal enamel formation in mice. Hum. Molec. Genet. 17: 3509-3520, 2008. [PubMed: 18703497] [Full Text: https://doi.org/10.1093/hmg/ddn243]
Boudghene-Stambouli, O., Merad-Boudia, A. Association dysplasie ectodermique et syndactylie. Ann. Derm. Venereol. 118: 107-110, 1991. [PubMed: 1646587]
Brancati, F., Fortugno, P., Bottillo, I., Lopez, M., Josselin, E., Boudghene-Stambouli, O., Agolini, E., Bernardini, L., Bellacchio, E., Iannicelli, M., Rossi, A., Dib-Lachachi, A., Stuppia, L., Palka, G., Mundlos, S., Stricker, S., Kornak, U., Zambruno, G., Dallapiccola, B. Mutations in PVRL4, encoding cell adhesion molecule nectin-4, cause ectodermal dysplasia-syndactyly syndrome. Am. J. Hum. Genet. 87: 265-273, 2010. [PubMed: 20691405] [Full Text: https://doi.org/10.1016/j.ajhg.2010.07.003]
Fabre-Lafay, S., Garrido-Urbani, S., Reymond, N., Goncalves, A., Dubreuil, P., Lopez, M. Nectin-4, a new serological breast cancer marker, is a substrate for tumor necrosis factor-alpha-converting enzyme (TACE)/ADAM-17. J. Biol. Chem. 280: 19543-19550, 2005. [PubMed: 15784625] [Full Text: https://doi.org/10.1074/jbc.M410943200]
Fortugno, P., Josselin, E., Tsiakas, K., Agolini, E., Cestra, G., Teson, M., Santer, R., Castiglia, D., Novelli, G., Dallapiccola, B., Kurth, I., Lopez, M., Zambruno, G., Brancati, F. Nectin-4 mutations causing ectodermal dysplasia with syndactyly perturb the Rac1 pathway and the kinetics of adherens junction formation. J. Invest. Derm. 134: 2146-2153, 2014. [PubMed: 24577405] [Full Text: https://doi.org/10.1038/jid.2014.119]
Hartz, P. A. Personal Communication. Baltimore, Md. 9/24/2010.
Jelani, M., Chishti, M. S., Ahmad, W. Mutation in PVRL4 gene encoding nectin-4 underlies ectodermal-dysplasia-syndactyly syndrome (EDSS1). J. Hum. Genet. 56: 352-357, 2011. [PubMed: 21346770] [Full Text: https://doi.org/10.1038/jhg.2011.18]
Muhlebach, M. D., Mateo, M., Sinn, P. L., Prufer, S., Uhlig, K. M., Leonard, V. H. J., Navaratnarajah, C. K., Frenzke, M., Wong, X. X., Sawatsky, B., Ramachandran, S., McCray, P. B., Jr., Cichutek, K., von Messling, V., Lopez, M., Cattaneo, R. Adherens junction protein nectin-4 is the epithelial receptor for measles virus. Nature 480: 530-533, 2011. [PubMed: 22048310] [Full Text: https://doi.org/10.1038/nature10639]
Raza, S. I., Nasser Dar, R., Shah, A. A., Ahmad, W. A novel homozygous nonsense mutation in the PVRL4 gene and expansion of clinical spectrum of EDSS1. Ann. Hum. Genet. 79: 92-98, 2015. Note: Erratum: Ann. Hum. Genet. 82: 52 only, 2018. [PubMed: 25529316] [Full Text: https://doi.org/10.1111/ahg.12094]
Reymond, N., Fabre, S., Lecocq, E., Adelaide, J., Dubreuil, P., Lopez, M. Nectin4/PRR4, a new Afadin-associated member of the nectin family that trans-interacts with nectin1/PRR1 through V domain interaction. J. Biol. Chem. 276: 43205-43215, 2001. [PubMed: 11544254] [Full Text: https://doi.org/10.1074/jbc.M103810200]