Alternative titles; symbols
HGNC Approved Gene Symbol: NID1
Cytogenetic location: 1q42.3 Genomic coordinates (GRCh38): 1:235,975,830-236,065,090 (from NCBI)
Entactin, a 150-kD sulfated glycoprotein, is a major component of basement membranes and forms a highly stable noncovalent complex with laminin (see 150320). Durkin et al. (1988) derived the complete amino acid sequence of mouse entactin from sequencing of cDNA clones.
Nagayoshi et al. (1989) reported the complete amino acid sequence, deduced structural domains, and RFLPs of human nidogen.
Bercsenyi et al. (2014) showed that the presence of nidogens (also known as entactins) at the neuromuscular junction is the main determinant for tetanus neurotoxin (TeNT) binding. Inhibition of the TeNT-nidogen interaction by using small nidogen-derived peptides or genetic ablation of nidogens prevented the binding of TeNT to neurons and protected mice from TeNT-induced spastic paralysis. Bercsenyi et al. (2014) concluded that their findings demonstrated the direct involvement of an extracellular matrix protein as a receptor for tetanus neurotoxin at the neuromuscular junction.
Durkin et al. (1995) found that the mouse entactin gene spans at least 65 kb and contains 20 exons. The exon organization of the mouse gene closely corresponds to the organization of the polypeptide into distinct structural and functional domains.
Zimmermann et al. (1995) characterized the human nidogen gene, which consists of 20 exons spanning at least 90 kb. The various protein subdomains were shown to be encoded by individual exons. A CpG island is present surrounding the first exon, from nucleotides -400 to +600 of the genomic sequence.
Chung and Durkin (1990) presented structural evidence that entactin can serve as a bridge between the 2 most abundant molecules in the basement membrane: type IV collagen (see 120130) and laminin.
Crystal Structure
Takagi et al. (2003) determined the crystal structure of the nidogen-1 G3-III complex with laminin at a resolution of 2.3 angstroms. The structure of the interacting domains revealed a 6-bladed tyr-trp-thr-asp (YWTD) beta-propeller domain in nidogen bound to laminin epidermal growth factor-like (LE) modules III3-5 (LE3-5) in laminin. Laminin LE module 4 (LE4) binds to an amphitheater-shaped surface on the pseudo-6-fold axis of the beta-propeller, and laminin LE3 binds over its rim. A phe residue that shutters the water-filled central aperture of the beta-propeller, the rigidity of the amphitheater, and high shape complementarity enabled the construction of an evolutionarily conserved binding surface for LE4 of unprecedentedly high affinity for its small size. Hypermorphic mutations in the Wnt coreceptor LRP5 (603506) suggested to Takagi et al. (2003) that a similar YWTD beta-propeller interface is used to bind ligands that function in developmental pathways. The LDLR protein (606945), which functions as an endocytic receptor, also contains a YWTD beta-propeller domain which, in contrast to that present in nidogen-1, lacks closure of the bottom of the binding pocket in the hub of the beta-propeller.
Mattei et al. (1989) used in situ hybridization to localize the human nidogen gene to chromosome 1q43. Olsen et al. (1989) reported the details of the mapping studies as well as expression studies.
Jenkins et al. (1991) mapped the nidogen gene (Nid) to mouse chromosome 13 and showed linkage to the beige (bg) mutation. The bg mutation is thought to be the mouse homolog of the Chediak-Higashi syndrome (CHS; 214500).
By analyzing sperm recombination, Jeffreys and Neumann (2005) determined that an NID1 hotspot was associated with a minisatellite, suggesting that hotspots may predispose DNA to tandem repetition. Unlike the neighboring MS32 hotspot, crossover resolution breakpoints in NID1 avoided the minisatellite, producing a coldspot within the hotspot. Close to the center of the NID1 hotspot, they identified a SNP, which they termed M-57.8T/C located 57.8 kb upstream of the MS32 hotspot, that appeared to directly influence the frequency of crossover initiation. Quantitative gene conversion assays showed that this SNP affected the frequency of gene conversion and crossover to a very similar extent, suggesting that conversions and crossovers may be triggered by the same recombination initiating events. The recombination-suppressing T allele was overtransmitted to recombinant progeny, and provided an example of recombination-mediated meiotic drive, of a magnitude sufficient to virtually guarantee that the recombination suppressor will eventually replace the more active C allele in human populations.
Associations Pending Confirmation
See 131390.0001 for discussion of a possible association between mutation in the NID1 gene and Dandy-Walker malformation with occipital cephalocele (ADDWOC; 609222).
Murshed et al. (2000) generated Nid1-deficient mice and determined that homozygous mice produced neither Nid1 mRNA nor protein. Surprisingly, the homozygous mice were fertile and their basement membranes appeared normal. However, Nid2 expression, normally only scant, was increased in certain basement membranes (e.g., striated muscle endothelium, heart, and kidney) without upregulating Nid2 production or changing the expression of perlecan (HSPG2; 142461) or laminin. The authors concluded that although NID1 is present in all normal basement membranes, it is, unlike LAMC1 (150290), not required for basement membrane formation or maintenance.
This variant is classified as a variant of unknown significance because its contribution to Dandy-Walker malformation with occipital cephalocele (ADDWOC; 609222) has not been confirmed.
In 14 affected members of a large 3-generation Vietnamese family with autosomal dominant Dandy-Walker malformation with occipital cephalocele, originally reported by Bassuk et al. (2004), Darbro et al. (2013) identified heterozygosity for a c.1162C-T transition (chr1:236,201,527; GRCh37) in the NID1 gene, resulting in a gln388-to-ter (Q388X) substitution predicted to result in loss of the entire G2 and G3 regions of NID1, including the beta-propeller domain that directly interacts with LAMC1 (150290). The mutation was not found in 384 Vietnamese control chromosomes or in the dbSNP (build 135), 1000 Genomes Project, or NHLBI Exome Sequencing Project databases. No functional analysis of the variant was reported.
Bassuk, A. G., McLone, D., Bowman, R., Kessler, J. A. Autosomal dominant occipital cephalocele. Neurology 62: 1888-1890, 2004. [PubMed: 15159504] [Full Text: https://doi.org/10.1212/01.wnl.0000125255.90915.5c]
Bercsenyi, K., Schmieg, N., Bryson, J. B., Wallace, M., Caccin, P., Golding, M., Zanotti, G., Greensmith, L., Nischt, R., Schiavo, G. Nidogens are therapeutic targets for the prevention of tetanus. Science 346: 1118-1123, 2014. [PubMed: 25430769] [Full Text: https://doi.org/10.1126/science.1258138]
Chung, A. E., Durkin, M. E. Entactin: structure and function. Am. J. Resp. Cell Molec. Biol. 3: 275-282, 1990. [PubMed: 2119632] [Full Text: https://doi.org/10.1165/ajrcmb/3.4.275]
Darbro, B. W., Mahajan, V. B., Gakhar, L., Skeie, J. M., Campbell, E., Wu, S., Bing, X., Millen, K. J., Dobyns, W. B., Kessler, J. A., Jalali, A., Cremer, J., and 14 others. Mutations in extracellular matrix genes NID1 and LAMC1 cause autosomal dominant Dandy-Walker malformation and occipital cephaloceles. Hum. Mutat. 34: 1075-1079, 2013. [PubMed: 23674478] [Full Text: https://doi.org/10.1002/humu.22351]
Durkin, M. E., Chakravarti, S., Bartos, B. B., Liu, S.-H., Friedman, R. L., Chung, A. E. Amino acid sequence and domain structure of entactin: homology with epidermal growth factor precursor and low density lipoprotein receptor. J. Cell Biol. 107: 2749-2756, 1988. [PubMed: 3264556] [Full Text: https://doi.org/10.1083/jcb.107.6.2749]
Durkin, M. E., Wewer, U. M., Chung, A. E. Exon organization of the mouse entactin gene corresponds to the structural domains of the polypeptide and has regional homology to the low-density lipoprotein receptor gene. Genomics 26: 219-228, 1995. [PubMed: 7601446] [Full Text: https://doi.org/10.1016/0888-7543(95)80204-y]
Jeffreys, A. J., Neumann, R. Factors influencing recombination frequency and distribution in a human meiotic crossover hotspot. Hum. Molec. Genet. 14: 2277-2287, 2005. [PubMed: 15987698] [Full Text: https://doi.org/10.1093/hmg/ddi232]
Jenkins, N. A., Justice, M. J., Gilbert, D. J., Chu, M.-L., Copeland, N. G. Nidogen/entactin (Nid) maps to the proximal end of mouse chromosome 13 linked to beige (bg) and identifies a new region of homology between mouse and human chromosomes. Genomics 9: 401-403, 1991. [PubMed: 1672300] [Full Text: https://doi.org/10.1016/0888-7543(91)90275-j]
Mattei, M.-G., Passage, E., Weil, D., Nagayoshi, T., Knowlton, R. G., Chu, M.-L., Uitto, J. Chromosomal mapping of human basement membrane zone genes: laminin A chain at locus 18p11.31 and nidogen at locus 1q43. (Abstract) Cytogenet. Cell Genet. 51: 1041 only, 1989.
Murshed, M., Smyth, N., Miosge, N., Karolat, J., Krieg, T., Paulsson, M., Nischt, R. The absence of nidogen 1 does not affect murine basement membrane formation. Molec. Cell. Biol. 20: 7007-7012, 2000. [PubMed: 10958695] [Full Text: https://doi.org/10.1128/MCB.20.18.7007-7012.2000]
Nagayoshi, T., Sanborn, D., Hickok, N. J., Olsen, D. R., Fazio, M. J., Chu, M.-L., Knowlton, R., Mann, K., Deutzmann, R., Timpl, R., Uitto, J. Human nidogen: complete amino acid sequence and structural domains deduced from cDNAs, and evidence for polymorphism of the gene. DNA 8: 581-594, 1989. [PubMed: 2574658] [Full Text: https://doi.org/10.1089/dna.1989.8.581]
Olsen, D. R., Nagayoshi, T., Fazio, M., Mattei, M.-G., Passage, E., Weil, D., Timpl, R., Chu, M.-L., Uitto, J. Human nidogen: cDNA cloning, cellular expression, and mapping of the gene to chromosome 1q43. Am. J. Hum. Genet. 44: 876-885, 1989. [PubMed: 2471408]
Takagi, J., Yang, Y., Liu, J., Wang, J., Springer, T. A. Complex between nidogen and laminin fragments reveals a paradigmatic beta-propeller interface. Nature 424: 969-974, 2003. [PubMed: 12931195] [Full Text: https://doi.org/10.1038/nature01873]
Zimmermann, K., Hoischen, S., Hafner, M., Nischt, R. Genomic sequences and structural organization of the human nidogen gene (NID). Genomics 27: 245-250, 1995. [PubMed: 7557988] [Full Text: https://doi.org/10.1006/geno.1995.1038]