Alternative titles; symbols
HGNC Approved Gene Symbol: EDAR
Cytogenetic location: 2q13 Genomic coordinates (GRCh38) : 2:108,894,471-108,989,220 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q13 | [Hair morphology 1, hair thickness] | 612630 | 3 | |
| Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant | 129490 | Autosomal dominant | 3 | |
| Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive | 224900 | Autosomal recessive | 3 |
Hypohidrotic ectodermal dysplasia (HED) results in abnormal morphogenesis of teeth, hair, and eccrine sweat glands. Autosomal recessive forms of the disorder exist at 2 separate loci ('crinkled,' cr, and 'downless,' dl) in mice. A candidate gene has been identified at the dl locus that is mutated in both dl and Dl(sleek) (Dl(slk)) mutant alleles. Monreal et al. (1999) isolated and characterized EDAR, the human Dl homolog. The putative protein is predicted to have a single transmembrane domain, and shows similarity to 2 separate domains of the tumor necrosis factor (TNF; 191160) receptor (TNFR) family. The DL gene encodes a protein of 448 amino acids that is 91% identical to the mouse dl. The protein contains a single transmembrane domain with a type 1 membrane topology (extracellular amino terminus).
Yan et al. (2000) found that EDAR binds only EDA-A1 (see EDA; 300451), an ectodysplasin isoform that encodes a 391-amino acid protein with a domain similar to TNF at the C terminus. They examined the expression of EDAR in developing mouse skin by in situ hybridization. At embryonic day 14, EDAR transcripts were clearly present in the basal cells of the developing epidermis, with elevated focal expression in placodes. By embryonic days 16 and 17, EDAR was expressed in large amounts in the maturing follicles. By postnatal day 1, the pattern of expression was confined to the hair follicles. In addition, Yan et al. (2000) identified an X-linked ectodysplasin receptor, XEDAR (300276), that binds to the EDA-A2 isoform of EDA. EDA-A2 is identical to EDA-A1 except for a 2-residue deletion of glu308 and val309 that is caused by an internal splice donor site.
Doffinger et al. (2001) demonstrated that DL triggers NF-kappa-B (see 164011) through the NEMO protein (300248), indicating that anhidrotic ectodermal dysplasia results from impaired NF-kappa-B signaling.
Elomaa et al. (2001) showed that ectodysplasin is released from cells to the culture medium, and that EDAR is able to coprecipitate EDA-A1, confirming that they form a ligand-receptor pair. In situ hybridization and immunostaining demonstrated that ectodysplasin and EDAR are expressed in adjacent or partially overlapping layers in the developing human skin. The authors concluded that as a soluble ligand ectodysplasin is able to interact with EDAR and mediate signals needed for the development of ectodermal appendages.
Trompouki et al. (2003) identified CYLD (605018) as a deubiquitinating enzyme that negatively regulates activation of NF-kappa-B by specific TNFRs. Loss of the deubiquitinating activity of CYLD correlated with tumorigenesis. CYLD inhibits activation of NF-kappa-B by the TNFR family members CD40 (109535), XEDAR, and EDAR in a manner that depends on deubiquitinating activity of CYLD. Downregulation of CYLD by RNA-mediated interference augments both basal and CD40-mediated activation of NF-kappa-B. The inhibition of NF-kappa-B activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TNFR-associated factor 2 (TRAF2; 601895) and, to a lesser extent, TRAF6 (602355). Trompouki et al. (2003) concluded that CYLD is a negative regulator of the cytokine-mediated activation of NF-kappa-B that is required for appropriate cellular homeostasis of skin appendages.
Using transfected human embryonic kidney cells and fibroblasts from mouse embryos defective in NF-kappa-B pathway components, Shindo and Chaudhary (2004) showed that EDAR signaling repressed LEF1 (153245)-beta-catenin (CTNNB1; 116806)-dependent transcription independent of its stimulatory effect on NF-kappa-B activity. Human EDAR with the arg420-to-gln (R420Q; 604095.0006) mutation associated with anhidrotic ectodermal dysplasia exhibited defects in both NF-kappa-B activation and LEF1/beta-catenin repression. In contrast, mouse Edar with a mutation associated with the downless phenotype retained significant ability to activate NF-kappa-B signaling and repress Lef1/beta-catenin activity. Shindo and Chaudhary (2004) concluded that, by stimulating NF-kappa-B activity and repressing LEF1/beta-catenin-dependent transcription, EDAR has opposing effects on 2 major and independent pathways involved in ectodermal differentiation and hair follicle morphogenesis. Since LEF1/beta-catenin controls expression of EDA, the results suggested negative feedback regulation of the EDA-EDAR axis.
Monreal et al. (1999) localized the EDAR gene to a position 10.1 cR from marker AFMA037YB9 between markers D2S293 and D2S121, an interval contained in chromosome 2q11-q13. Autosomal recessive hypohidrotic ectodermal dysplasia (HED; 224900) does not map to the candidate gene locus in all families, implying the existence of at least 1 additional human locus.
Sabeti et al. (2007) reported an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2. The analysis revealed more than 300 strong candidate regions that appeared to have undergone recent natural selection. Examination of 22 of the strongest regions highlighted 3 cases in which 2 genes in a common biologic process had apparently undergone positive selection in the same population: LARGE (603590) and DMD (300377), both related to infection by the Lassa virus, in West Africa; SLC24A5 (609802) and SLC45A2 (606202), both involved in skin pigmentation, in Europe; and EDAR and EDA2R (300276), both involved in the development of hair follicles, in Asia.
Monreal et al. (1999) identified mutations in the DL gene in 3 families displaying recessive inheritance of HED (ECTD10B; 224900) and 2 with dominant inheritance (ECTD10A; 129490). They identified 7 variants, 2 of which were detected in the control population. A single change involving a basepair transition in exon 12 (arg358 to ter, 604095.0005; arg420 to gln, 604095.0006) was found in each dominant family. The arg358-to-ter mutation resulted in a truncation of the predicted cytoplasmic portion of the protein, similar to the effect of the dominant mutation Dl(slk) in the mouse, which truncates the protein before the possible death domain. It had been shown that coexpression of a truncated TNFR with a wildtype receptor results in a dominant-negative effect on function, presumably due to lack of homotrimerization of the death domains. Dominant-negative mutations have also been described in the FAS antigen (134637), a member of the TNFR family, in patients with autoimmune lymphoproliferative syndrome (601859). The nonconserved missense mutation arg420 to gln in a second family was also in the predicted cytoplasmic portion of the protein within the potential death domain. Monreal et al. (1999) showed that DL mutations produce recessive loss-of-function, as well as likely dominant-negative, effects. One hypothesis is that the protein functions as a multimeric receptor and is related to the TNFR family. The authors noted that ectodysplasin-A, the protein abnormal in X-linked hypohidrotic ectodermal dysplasia, shows a highly significant match in its extracellular domain with the TNF family profile. Further study will be required to test if DL and ectodysplasin-A proteins function as receptor and ligand in a common signaling pathway.
To assess the role of the EDAR gene in HED, Chassaing et al. (2006) screened for mutations in 37 unrelated HED families or sporadic cases with no detected mutations in the EDA gene (300451). They identified 11 different mutations, 9 of which were novel variants, in 2 familial and 7 sporadic cases. Seven of the 11 were recessive and the other 4 were considered to be probably dominant. The study demonstrated that EDAR is implicated in about 25% of non-EDA HED. They diagrammed the process by which, during hair follicle morphogenesis, EDAR is activated by the product of the EDA gene and uses EDARADD (606603) as an adaptor to activate the NF-kappa-B (see 164011) signaling pathway (Mikkola and Thesleff, 2003).
In an 18-year-old Lebanese woman with a severe form of autosomal recessive anhidrotic ectodermal dysplasia with unusual clinical features including absence of breasts, extranumerary areola and nipple on the left side, and marked palmoplantar hyperkeratosis, Megarbane et al. (2008) identified a novel homozygous splice site mutation in the EDAR gene (IVS9+G-A; 604095.0013). RT-PCR analysis performed on whole skin biopsies and genes known to be expressed in skin appendages indicated that the mutation severely impairs EDAR cDNA splicing, resulting in total absence of EDAR transcripts and consequently of the EDAR protein. Megarbane et al. (2008) hypothesized that the mutation leads to the loss of EDAR/NF-kappa-B signaling. They speculated that the mutation impairs Wnt (see 164820)/B-catenin (116806) downregulation, which may modify the balance between signals necessary to mammary gland development.
Fujimoto et al. (2008) identified a mutation in the EDAR gene associated with variation in hair thickness (604095.0011).
Headon and Overbeek (1999) used positional cloning to identify the mouse dl gene, which encodes a novel member of the tumor necrosis factor receptor family. The mutant phenotype and dl expression pattern suggested that this gene encodes a receptor that specifies hair follicle fate. Its ligand is likely to be the product of the 'Tabby' gene, as Ta mutants have a phenotype identical to that of dl mutants and Ta encodes a tumor necrosis factor receptor-like protein. Northern blot analysis of mRNA from embryonic day 17.5 skin revealed a 3.8-kb transcript in all genotypes except Dl(slk) and dl(OVE1B). At embryonic day 13, before hair follicle induction, dl is expressed throughout the basal layer of the epidermis. By embryonic day 15, expression has become upregulated in foci of induced cells initiating and undergoing follicular morphogenesis and is beginning to be downregulated in surrounding cells. By embryonic day 17, dl is expressed in secondary follicles and elongating primary follicles, but is no longer detected in the interfollicular epidermis. There was an absence of expression of early hair follicle markers, including Bmp4 and Shh, in dl mutant skin.
By examining embryonic mouse skin cultures, Mou et al. (2006) determined that Edar is central to the generation of the primary hair follicle pattern. They found a rapid Edar-positive feedback mechanism in the epidermis coupled with induction of dermal Bmp4 (112262) and Bmp7 (112267), which repressed epidermal Edar expression and follicle fate in cells neighboring nascent follicles. Edar activation also induced connective tissue growth factor (CTGF; 121009), an inhibitor of BMP signaling, allowing BMP action only at a distance from nascent follicles. Consistent with this mode, transgenic hyperactivation of Edar signaling led to widespread overproduction of hair follicles. Edar-mediated stabilization of beta-catenin (see CTNNB1, 116806)-active foci appeared to be a key event in determining follicle location.
Mou et al. (2008) found that mice with overexpression of the Edar gene displayed a coarser coat hair phenotype compared to wildtype mice. The diameter of each hair type was increased by 10 to 25% upon elevation of Edar signaling, corresponding to an increase of cross-sectional area of 21 to 56%. In addition, the hair of transgenic mice showed increased straightness and a more circular cross-section appearance. Primary hair follicles of the transgenic mice showed an enlarged bulb region with Edar expression within the bulb, and transgenic mouse embryos showed larger hair follicle placodes, which represent the organ primordia. Mou et al. (2008) commented that the phenotype was similar to that observed in East Asian human hair, which is thicker and more circular on cross-section profile and is associated with a SNP in the EDAR gene (604095.0011) that causes increased downstream NFKB activity.
In a consanguineous family with autosomal recessive hypohidrotic ectodermal dysplasia (ECTD10B; 224900), Monreal et al. (1999) identified an 18-bp deletion at the 3-prime end of intron 2 of the EDAR gene. The deletion altered 7 of 10 basepairs constituting a polypyrimidine stretch at the acceptor splice site, reducing the number of pyrimidines from 8 to 3.
In 2 affected sibs from a nonconsanguineous family with autosomal recessive hypohidrotic ectodermal dysplasia (ECTD10B; 224900), Monreal et al. (1999) detected a G-to-A transition at nucleotide 266 of the EDAR gene resulting in a nonconservative change of arg89 to his in the extracellular domain. The affected children were heterozygous at flanking polymorphic loci, but failed to inherit a paternal allele at the D2S1893 locus. Sequencing revealed their mother to be heterozygous for the variant, whereas their father was hemizygous wildtype. Thus, the affected individuals were compound heterozygotes, with their paternal allele containing a large deletion of indeterminate size (see 604095.0003).
Van der Hout et al. (2008) reported 2 brothers with hypohidrotic ectodermal dysplasia resulting from compound heterozygosity for the R89H and D110A (604095.0009) mutations in the EDAR gene. The unaffected father carried the D110A mutation. However, the mother, who was heterozygous for the R89H mutation, was mildly affected with hypohidrosis and few permanent teeth, consistent with autosomal dominant hypohidrotic ectodermal dysplasia (ECTD10A; 129490). Van der Hout et al. (2008) concluded that some presumably 'recessive' mutations may show phenotypic expression in carriers.
For discussion of the large deletion of indeterminate size that was found in the EDAR gene in compound heterozygous state in 2 sibs with autosomal recessive hypohidrotic ectodermal dysplasia (ECTD10B; 224900) by Monreal et al. (1999), see 604095.0002.
In a family with autosomal recessive hypohidrotic ectodermal dysplasia (ECTD10B; 224900), Monreal et al. (1999) identified a homozygous T-to-C transition at nucleotide 259 of the EDAR gene resulting in a cys-to-arg substitution at codon 87 (C87R) in affected individuals. The mutation resulted in a nonconservative change in the extracellular domain, possibly affecting intra- or interchain disulfide bond formation.
In a family with autosomal dominant hypohidrotic ectodermal dysplasia (ECTD10A; 129490), Monreal et al. (1999) identified a C-to-T transition at nucleotide 1072 in exon 12 of the EDAR gene resulting in an arg-to-ter substitution at codon 358 (R358X). This mutation was found in heterozygosity in all affected individuals. The mutation resulted in a truncation of the predicted cytoplasmic portion of the protein, similar to the effect of the dominant mutation Dl(slk) in the mouse, which truncates the protein before the possible death domain.
In all affected members of a family with autosomal dominant hypohidrotic ectodermal dysplasia (ECTD10A; 129490), Monreal et al. (1999) identified a G-to-A transition at nucleotide 1259 in exon 12 of the EDAR gene that resulted in an arg-to-gln substitution at codon 420 (R420Q).
In a Japanese woman with autosomal recessive hypohidrotic ectodermal dysplasia (ECTD10B; 224900), Shimomura et al. (2004) identified compound heterozygosity for 2 mutations in the EDAR gene: a G-to-A transition in intron 2, resulting in an unstable transcript lacking exon 2, and a 1124G-A transition in exon 12, resulting in an arg375-to-his (R375H; 604095.0008) substitution within the intracellular DD domain. The patient's unaffected father carried the R375H mutation. In vitro functional expression studies showed that the R375H mutant protein did not interact with EDARADD (606603) and was functionally inactive. The patient had heat intolerance, sparse hair, periorbital wrinkling, and oligodontia.
For discussion of the arg357-to-his (R357H) mutation in the EDAR gene that was found in compound heterozygous state in a patient with autosomal recessive hypohidrotic ectodermal dysplasia (ECTD10B; 224900) by Shimomura et al. (2004), see 604095.0007.
In 2 brothers with autosomal recessive hypohidrotic ectodermal dysplasia (ECTD10B; 224900), van der Hout et al. (2008) identified compound heterozygosity for 2 mutations in the EDAR gene: a 329A-C transversion in exon 4 resulting in an asp110-to-ala (D110A) substitution and the R89H (604095.0002) mutation. The unaffected father was heterozygous for the D110A mutation.
In a woman with autosomal dominant hypohidrotic ectodermal dysplasia (ECTD10A; 129490), van der Hout et al. (2008) identified a heterozygous 1060G-T transversion in exon 12 of the EDAR gene, resulting in a glu354-to-ter (E354X) substitution. Her son was also affected but was not tested for the mutation.
Fujimoto et al. (2008) identified a 1540T-C SNP (rs3827760) in exon 12 of the EDAR gene, resulting in a val370-to-ala (V370A) substitution in the intracellular death domain. The C allele was present at a frequency of 87.6% in 180 Chinese and Japanese samples, compared to 0% in 120 European and African samples. A further study of 121 unrelated Indonesian individuals from the Java Island and 65 unrelated individuals of the Thai-Mai in Thailand showed a significant association of the 1540T/C SNP with cross-sectional area of hairs (612630) (p = 5.5 x 10(-3) and p = 9.5 x 10(-4), for the populations, respectively). In vitro functional expression studies showed that the C allele of this SNP in EDAR resulted in decreased downstream activity of NFKB (see 164011) 48 hours after transfection into HeLa cells. By studying the geographic distribution of the 1540T/C SNP in the EDAR gene and using haplotype analysis, Fujimoto et al. (2008) concluded that the 1540C allele arose after the divergence of Asians from Europeans, and that its frequency has rapidly increased in East Asian populations due to positive selection.
In a follow-up study, Fujimoto et al. (2008) found a significant association between 1540C and increased hair cross-sectional area in a cohort of 189 Japanese individuals (p = 2.7 x 10(-6)). A stronger association was noted (p = 3.8 x 10(-10)) when the findings were combined with population results of the Thai-Mai and Indonesian cohorts from the previous study. The findings confirmed that EDAR is the genetic determinant of hair thickness, as well as a strong contributor to hair fiber thickness variation, in East Asian populations.
In contrast to the findings of Fujimoto et al. (2008), Mou et al. (2008) found that the C allele (ala370) resulted in increased downstream activity of NFKB in transfected human cells after 18 hours. Mou et al. (2008) stated that their results more accurately reflected physiologic conditions.
For discussion of a possible association between the T1540C polymorphism and shovel-shaped incisors, see 147400.
In affected members of a consanguineous Pakistani family with autosomal recessive hypohidrotic ectodermal dysplasia (ECTD10B; 224900), Naeem et al. (2005) identified a homozygous 4-bp deletion (718delAAAG) in exon 8 of the EDAR gene, resulting in a frameshift and premature termination. Affected individuals had classic features of the disorder, including sparse hair, absent eyebrows and eyelashes, missing teeth, decreased sweating, dry thin skin, periorbital wrinkling and hyperpigmentation, prominent lips, and a saddle-shaped nose. Heterozygous gene carriers were not affected. Naeem et al. (2005) postulated that the mutation resulted in nonsense-mediated mRNA decay with complete absence of the protein.
In an 18-year-old Lebanese woman with a severe form of autosomal recessive anhidrotic ectodermal dysplasia (ECTD10B; 224900) with unusual clinical features including absence of breasts, extranumerary areola and nipple on the left side, and marked palmoplantar hyperkeratosis, Megarbane et al. (2008) identified a novel homozygous splice site mutation in the EDAR gene (IVS9+G-A). RT-PCR analysis performed on whole skin biopsies and genes known to be expressed in skin appendages indicated that the mutation severely impairs EDAR cDNA splicing, resulting in total absence of EDAR transcripts and consequently of the EDAR protein. Megarbane et al. (2008) stated that this was the first complete loss-of-function mutation identified in the EDAR gene, which may explain the unusual presentation of EDA in this patient.
Chassaing, N., Bourthoumieu, S., Cossee, M., Calvas, P., Vincent, M.-C. Mutations in EDAR account for one-quarter of non-ED1-related hypohidrotic ectodermal dysplasia. Hum. Mutat. 27: 255-259, 2006. [PubMed: 16435307] [Full Text: https://doi.org/10.1002/humu.20295]
Doffinger, R., Smahi, A., Bessia, C., Geissmann, F., Feinberg, J., Durandy, A., Bodemer, C., Kenwrick, S., Dupuis-Girod, S., Blanche, S., Wood, P., Rabia, S. H., and 16 others. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa-B signaling. Nature Genet. 27: 277-285, 2001. [PubMed: 11242109] [Full Text: https://doi.org/10.1038/85837]
Elomaa, O., Pulkkinen, K., Hannelius, U., Mikkola, M., Saarialho-Kere, U., Kere, J. Ectodysplasin is released by proteolytic shedding and binds to the EDAR protein. Hum. Molec. Genet. 10: 953-962, 2001. [PubMed: 11309369] [Full Text: https://doi.org/10.1093/hmg/10.9.953]
Fujimoto, A., Kimura, R., Ohashi, J., Omi, K., Yuliwulandari, R., Batubara, L., Mustofa, M. S., Samakkarn, U., Settheetham-Ishida, W., Ishida, T., Morishita, Y., Furusawa, T., Nakazawa, M., Ohtsuka, R., Tokunaga, K. A scan for genetic determinants of human hair morphology: EDAR is associated with Asian hair thickness. Hum. Molec. Genet. 17: 835-843, 2008. [PubMed: 18065779] [Full Text: https://doi.org/10.1093/hmg/ddm355]
Fujimoto, A., Ohashi, J., Nishida, N., Miyagawa, T., Morishita, Y., Tsunoda, T., Kimura, R., Tokunaga, K. A replication study confirmed the EDAR gene to be a major contributor to population differentiation regarding head hair thickness in Asia. Hum. Genet. 124: 179-185, 2008. [PubMed: 18704500] [Full Text: https://doi.org/10.1007/s00439-008-0537-1]
Headon, D. J., Overbeek, P. A. Involvement of a novel Tnf receptor homologue in hair follicle induction. Nature Genet. 22: 370-374, 1999. [PubMed: 10431242] [Full Text: https://doi.org/10.1038/11943]
Megarbane, H., Cluzeau, C., Bodemer, C., Fraitag, S., Chababi-Atallah, M., Megarbane, A., Smahi, A. Unusual presentation of a severe autosomal recessive anhydrotic (sic) ectodermal dysplasia with a novel mutation in the EDAR gene. Am. J. Med. Genet. 146A: 2657-2662, 2008. [PubMed: 18816645] [Full Text: https://doi.org/10.1002/ajmg.a.32509]
Mikkola, M. L., Thesleff, I. Ectodysplasin signaling in development. Cytokine Growth Factor Rev. 14: 211-224, 2003. [PubMed: 12787560] [Full Text: https://doi.org/10.1016/s1359-6101(03)00020-0]
Monreal, A. W., Ferguson, B. M., Headon, D. J., Street, S. L., Overbeek, P. A., Zonana, J. Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nature Genet. 22: 366-369, 1999. [PubMed: 10431241] [Full Text: https://doi.org/10.1038/11937]
Mou, C., Jackson, B., Schneider, P., Overbeek, P. A., Headon, D. J. Generation of the primary hair follicle pattern. Proc. Nat. Acad. Sci. 103: 9075-9080, 2006. [PubMed: 16769906] [Full Text: https://doi.org/10.1073/pnas.0600825103]
Mou, C., Thomason, H. A., Willan, P. M., Clowes, C., Harris, W. E., Drew, C. F., Dixon, J., Dixon, M. J., Headon, D. J. Enhanced ectodysplasin-A receptor (EDAR) signaling alters multiple fiber characteristics to produce the East Asian hair form. Hum. Mutat. 29: 1405-1411, 2008. [PubMed: 18561327] [Full Text: https://doi.org/10.1002/humu.20795]
Naeem, M., Muhammad, D., Ahmad, W. Novel mutations in the EDAR gene in two Pakistani consanguineous families with autosomal recessive hypohidrotic ectodermal dysplasia. Brit. J. Derm. 153: 46-50, 2005. [PubMed: 16029325] [Full Text: https://doi.org/10.1111/j.1365-2133.2005.06642.x]
Sabeti, P. C., Varilly, P., Fry, B., Lohmueller, J., Hostetter, E., Cotsapas, C., Xie, X., Byrne, E. H., McCarroll, S. A., Gaudet, R., Schaffner, S. F., Lander, E. S., International HapMap Consortium. Genome-wide detection and characterization of positive selection in human populations. Nature 449: 913-918, 2007. [PubMed: 17943131] [Full Text: https://doi.org/10.1038/nature06250]
Shimomura, Y., Sato, N., Miyashita, A., Hashimoto, T., Ito, M., Kuwano, R. A rare case of hypohidrotic ectodermal dysplasia caused by compound heterozygous mutations in the EDAR gene. J. Invest. Derm. 123: 649-655, 2004. [PubMed: 15373768] [Full Text: https://doi.org/10.1111/j.0022-202X.2004.23405.x]
Shindo, M., Chaudhary, P. M. The ectodermal dysplasia receptor represses the Lef-1/beta-catenin-dependent transcription independent of NF-kappa-B activation. Biochem. Biophys. Res. Commun. 315: 73-78, 2004. [PubMed: 15013427] [Full Text: https://doi.org/10.1016/j.bbrc.2004.01.025]
Trompouki, E., Hatzivassiliou, E., Tsichritzis, T., Farmer, H., Ashworth, A., Mosialos, G. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappa-B activation by TNFR family members. Nature 424: 793-796, 2003. [PubMed: 12917689] [Full Text: https://doi.org/10.1038/nature01803]
Van der Hout, A. H., Oudesluijs, G. G., Venema, A., Verheij, J. B. G. M., Mol, B. G. J., Rump, P., Brunner, H. G., Vos, Y. J., van Essen, A. J. Mutation screening of the ectodysplasin-A receptor gene EDAR in hypohidrotic ectodermal dysplasia. Europ. J. Hum. Genet. 16: 673-679, 2008. [PubMed: 18231121] [Full Text: https://doi.org/10.1038/sj.ejhg.5202012]
Yan, M., Wang, L.-C., Hymowitz, S. G., Schilbach, S., Lee, J., Goddard, A., de Vos, A. M., Gao, W.-Q., Dixit, V. M. Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors. Science 290: 523-527, 2000. [PubMed: 11039935] [Full Text: https://doi.org/10.1126/science.290.5491.523]