Alternative titles; symbols
HGNC Approved Gene Symbol: NECTIN1
SNOMEDCT: 716248001;
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38): 11:119,638,098-119,729,200 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.3 | Cleft lip/palate-ectodermal dysplasia syndrome | 225060 | Autosomal recessive | 3 |
| Orofacial cleft 7 | 225060 | Autosomal recessive | 3 |
Nectin-1 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)).
Members of the immunoglobin (Ig) superfamily have been shown to serve as receptors for various viruses. The human poliovirus receptor (PVR; 173850) is an integral membrane protein with one V-like extracellular Ig domain, 2 C-like extracellular Ig domains, a transmembrane region, and an intracytoplasmic region. Lopez et al. (1995) isolated a cDNA for a poliovirus receptor related gene, which they symbolized PRR. The predicted protein is 518 amino acids long and has a domain structure similar to PVR. In the extracellular domain, PRR is nearly 52% identical to PVR and 54% identical to the murine homolog of PVR. Northern blots showed a major 5.9-kb mRNA in all tissues tested.
Using the Don Chinese hamster line, Carritt and Goldfarb (1976) found that susceptibility to herpesvirus is determined by a gene on chromosome 3. Francke and Francke (1979) used a V79 line and concluded that human chromosome 11 is responsible for susceptibility; Don and V79 did not complement.
Geraghty et al. (1998) showed that poliovirus receptor-related protein-1 mediated entry of several alphaherpesviruses, including herpes simplex viruses (HSV) 1 and 2, porcine pseudorabies virus (PRV), and bovine herpesvirus 1 (BHV-1) into cells. The poliovirus receptor itself mediated entry of PRV and BHV-1, but not of the HSV strains tested by Geraghty et al. (1998). They found that PVRR1 was expressed in human cells of epithelial and neuronal origin and concluded that it is a prime candidate for the coreceptor that allows both HSV-1 and HSV-2 to infect epithelial cells on mucosal surfaces and spread to cells of the nervous system.
Using immunolocalization of adult mouse hippocampal sections Mizoguchi et al. (2002) found that the nectin-afadin system colocalizes with the cadherin (see 192090)-catenin (see 116805) system at synapses between mossy fiber terminals and dendrites of pyramidal cells in the CA3 area. Nectins-1 and -3 (PVRL3; 607147) asymmetrically localize at the pre- and postsynaptic sides of puncta adherentia junctions, respectively. During development, nectins-1 and -3 asymmetrically localize not only at puncta adherentia junctions but also at synaptic junctions. Using rat hippocampal neurons in culture, Mizoguchi et al. (2002) observed that inhibition of the nectin-based adhesion results in a decrease in synapse size and a concomitant increase in synapse number.
Togashi et al. (2011) found that mouse hair cells and supporting cells express the immunoglobulin-like adhesion molecules nectin-1 and -3, respectively, and that their interaction mediates the heterotypic adhesion between these 2 cell types. Genetic removal of nectin-1 or -3 disrupted the checkerboard-like pattern, inducing aberrant attachment between hair cells. When cells expressing either nectin-1 or -3 were cocultured, they arranged themselves into a mosaic pattern. Thus, Togashi et al. (2011) concluded that nectin-1 and nectin-3 promote the formation of the checkerboard-like pattern of the auditory epithelia.
Lopez et al. (1995) mapped the PVRR gene to 11q23-q24 by in situ hybridization.
Cleft Lip/Palate-Ectodermal Dysplasia Syndrome
The cleft lip/palate-ectodermal dysplasia syndrome (CLPED1; 225060), which has also been called both Zlotogora-Ogur syndrome and Margarita Island ectodermal dysplasia, is characterized clinically by cleft lip/palate, hidrotic ectodermal dysplasia, developmental defects of the hands, and, in some cases, mental retardation. Although generally rare, CLPED1 occurs with a frequency of approximately 1 per 2,000 among the indigenous population of Margarita Island, in whom Suzuki et al. (1998) assigned the CLPED1 locus to 11q23 by linkage mapping. Suzuki et al. (2000) genotyped markers spanning the CLPED1 interval in an inbred Israeli family with a diagnosis of Zlotogora-Ogur syndrome. The proband was homozygous and the first-cousin parents heterozygous for all markers tested, but with a different disease-associated haplotype than in Margarita Island families, consistent with allelism between Margarita Island and Israeli CLPED1. Suzuki et al. (2000) followed a positional cloning approach to identify the CLPED1 gene as PVRL1, encoding nectin-1, an immunoglobulin-related transmembrane cell-cell adhesion molecule that is part of the NAP cell adhesion system. Nectin-1 is also the principal cell surface receptor for alpha-herpesviruses (Geraghty et al., 1998). Suzuki et al. (2000) speculated that the high frequency of CLPED1 on Margarita Island in the Caribbean Sea might have resulted from resistance of heterozygotes to infection by these viruses.
In Margarita Island CLPED1 patients, Suzuki et al. (2000) identified a nonsense mutation (W185X; 600644.0001) in the PVRL1 gene.
In a 7-year-old Japanese boy with cleft lip/palate-ectodermal dysplasia syndrome who did not have any sequence variants in the TP63 gene (191170), Yoshida et al. (2015) identified a novel homozygous nonsense mutation in the NECTIN1 gene (R134X; 600644.0004). The consanguineous parents were heterozygous for the mutation. The authors noted that all 4 mutations identified in patients with CLPED1 cause truncated proteins that lack the transmembrane and intracellular domains. Loss of the intracellular domain might disrupt the protein-protein interactions needed to initiate the cell-cell adhesion process.
Orofacial Cleft 7
Sozen et al. (2001) demonstrated a highly significant association between heterozygosity for the W185X mutation and sporadic, nonsyndromic cleft lip with or without cleft palate (OFC7; see 225060) in northern Venezuela.
Barron et al. (2008) found that nectin-1 -/- mice were viable and fertile, but manifested microphthalmia and defective amelogenesis of their incisor teeth. Nectin-1 -/- incisors lacked the normal iron pigmentation characteristic of rodent enamel and were prone to wear and breakage. Immunohistochemical analysis of wildtype mice showed nectin-1 staining at the interface between the maturation-stage ameloblasts and the underlying cells of the stratum intermedium. In the absence of nectin-1, these cell layers were separated. Numerous large desmosomes were present at this interface in wildtype mice; however, where adhesion persisted in nectin-1 -/- mice, the desmosomes were smaller and less numerous. Barron et al. (2008) concluded that nectin-1 participates in desmosome assembly.
In Margarita Island patients with cleft lip/palate-ectodermal dysplasia syndrome (CLPED1; 225060), Suzuki et al. (2000) identified a homozygous nonsense mutation of codon trp185 (TGG to TAG) in the PVRL1 gene.
Sozen et al. (2001) demonstrated a highly significant association between heterozygosity for the W185X mutation and nonsyndromic, sporadic cleft lip with or without cleft palate (see 119530) in northern Venezuela. In the Cumana region of northern Venezuela, 14 (5.8%) of 243 individuals with cleft lip with or without cleft palate carried this mutation, versus 1 of 245 controls (0.4%) (p = 0.00039).
In an Israeli family with cleft lip/palate-ectodermal dysplasia (CLPED1; 225060) reported by Zlotogora et al. (1987), Suzuki et al. (2000) identified a homozygous deletion of 1 guanine from codon 185 (trp) of the PVRL1 gene, converting TGG to T-G and resulting in a frameshift. Notably this involved the same codon as was involved in a nonsense mutation in the Margarita Island CLEPD1 patients (600644.0001).
In a Brazilian family with cleft lip/palate-ectodermal dysplasia syndrome (CLPED1; 225060), Suzuki et al. (2000) identified a homozygous single-base duplication in codon gly323 of the PVRL1 gene (GGT to GGTT), resulting in frameshift.
In a 7-year-old Japanese boy with cleft lip/palate-ectodermal dysplasia (CLPED1; 225060), born to consanguineous parents, Yoshida et al. (2015) identified a homozygous c.400C-T transition in exon 2 of the NECTIN1 gene, resulting in an arg134-to-ter (R134X) substitution. The parents were heterozygous for the mutation, which was not found among 100 healthy Japanese controls. The patient did not have any sequence variants in the TP63 gene (191170). No functional studies were reported.
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]
Carritt, B., Goldfarb, P. Human chromosomal determinant for susceptibility to HSV. Nature 264: 556-558, 1976. [PubMed: 1034214] [Full Text: https://doi.org/10.1038/264556a0]
Francke, U., Francke, B. R. Assignment of gene(s) required for Herpes simplex virus type 1 (HV1S) replication to human chromosome 11. (Abstract) Cytogenet. Cell Genet. 25: 155 only, 1979.
Geraghty, R. J., Krummenacher, C., Cohen, G. H., Eisenberg, R. J., Spear, P. G. Entry of alphaherpesviruses mediated by poliovirus receptor-related protein 1 and poliovirus receptor. Science 280: 1618-1620, 1998. [PubMed: 9616127] [Full Text: https://doi.org/10.1126/science.280.5369.1618]
Lopez, M., Eberle, F., Mattei, M. G., Gabert, J., Birg, F., Bardin, F., Maroc, C., Dubreuil, P. Complementary DNA characterization and chromosomal localization of a human gene related to the poliovirus receptor-encoding gene. Gene 155: 261-265, 1995. [PubMed: 7721102] [Full Text: https://doi.org/10.1016/0378-1119(94)00842-g]
Mizoguchi, A., Nakanishi, H., Kimura, K., Matsubara, K., Ozaki-Kuroda, K., Katata, T., Honda, T., Kiyohara, Y., Heo, K., Higashi, M., Tsutsumi, T., Sonoda, S., Ide, C., Takai, Y. Nectin: an adhesion molecule involved in formation of synapses. J. Cell Biol. 156: 555-565, 2002. [PubMed: 11827984] [Full Text: https://doi.org/10.1083/jcb.200103113]
Sozen, M. A., Suzuki, K., Tolarova, M. M., Bustos, T., Fernandez Iglesias, J. E., Spritz, R. A. Mutation of PVRL1 is associated with sporadic, non-syndromic cleft lip/palate in northern Venezuela. Nature Genet. 29: 141-142, 2001. [PubMed: 11559849] [Full Text: https://doi.org/10.1038/ng740]
Suzuki, K., Bustos, T., Spritz, R. A. Linkage disequilibrium mapping of the gene for Margarita Island ectodermal dysplasia (ED4) to 11q23. Am. J. Hum. Genet. 63: 1102-1107, 1998. [PubMed: 9758630] [Full Text: https://doi.org/10.1086/302072]
Suzuki, K., Hu, D., Bustos, T., Zlotogora, J., Richieri-Costa, A., Helms, J. A., Spritz, R. A. Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia. Nature Genet. 25: 427-430, 2000. [PubMed: 10932188] [Full Text: https://doi.org/10.1038/78119]
Togashi, H., Kominami, K., Waseda, M., Komura, H., Miyoshi, J., Takeichi, M., Takai, Y. Nectins establish a checkerboard-like cellular pattern in the auditory epithelium. Science 333: 1144-1147, 2011. [PubMed: 21798896] [Full Text: https://doi.org/10.1126/science.1208467]
Yoshida, K., Hayashi, R., Fujita, H., Kubota, M., Kondo, M., Shimomura, Y., Niizeki, H. Novel homozygous mutation, c.400C-T (p.arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient. J. Derm. 42: 715-719, 2015. [PubMed: 25913853] [Full Text: https://doi.org/10.1111/1346-8138.12882]
Zlotogora, J., Zilberman, Y., Tenenbaum, A., Wexler, M. R. Cleft lip and palate, pili torti, malformed ears, partial syndactyly of fingers and toes and mental retardation: a new syndrome? J. Med. Genet. 24: 291-293, 1987. [PubMed: 3035184] [Full Text: https://doi.org/10.1136/jmg.24.5.291]