OMIA 000543-9615 : Anhidrotic ectodermal dysplasia, EDA-related in Canis lupus familiaris
In other species: cattle
Category: Integument (skin) phene
Links to MONDO diseases:
Mendelian trait/disorder: yes
Mode of inheritance: X-linked recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2005
Species-specific name: Ectodermal dysplasia, X-linked; X-linked hypohidrotic ectodermal dysplasia (XLHED); congenital hypotrichosis
Species-specific symbol: XHED
Species-specific description: X-linked ectodermal dysplasia is an inherited skin condition characterized by absent or abnormal teeth, hypotrichosis, and absent sweat glands. Other signs include decreased tear production, decreased mucociliary clearance, and symmetrical hairlessness. Affected animals are more susceptible to pulmonary infectious disease than normal dogs. Chronic nasal and ocular discharges are common, as are corneal ulceration and chronic demodecosis. The causative mutation is a point mutation in the ectodysplasin (EDA, also called ED1) gene. The mode of inheritance is X-linked recessive. Breeding of affected animals or known carriers is not recommended.
Edited by Dr. Margret Casal
Inheritance: Casal et al. (1997) showed that this disorder is X-linked recessive. Mosaic expression in females heterozygous for the causative mutation is possible (Casal et al., 2005).
Moura et al. (2020) reported an interesting case of an affected male and its mother, both of whom were dead by the time the researchers gained access to the data, which precluded any DNA testing. From pedigree information alone, Moura et al. (2020) reported that "Through Bayesian inference, it was possible to establish that this case originated from a new mutation, with a 99.99% probability of the mother of the proband not being a carrier."
Mapping: A linkage analysis with 5 markers evenly spaced along the length of the X chromosome enabled Casal et al. (2005) to show that the XHED locus is located near the centromere, very near to one of the two comparative candidate genes, namely EDA (ectodysplasin).
Molecular basis: By adopting a comparative positional cloning approach, involving a linkage analysis as described in the Mapping section, Casal et al. (2005) discovered that the causative mutation of XHED in the colony of German shepherd dogs described by Casal et al. (1997) is a "nucleotide substitution (G to A) in the splice acceptor site of intron 8 . . . In the presence of the A residue, a cryptic acceptor site within exon 9 is used, leading to a frame shift and use of a premature stop codon that truncates the translation of both isoforms, EDA-A1 and EDA-A2, resulting in the absence of the TNF-like homology domain, the receptor-binding site of ectodysplasin." Using the genetic variant nomenclature of 2015, the causative variant can be described as c.910-1G>A (OMIA variant 361).
In each of three affected mixed-breed dogs (two of which were brothers) from Israel, Waluk et al. (2016) reported that "the whole genome sequence data did not reveal any non-synonymous EDA variant in the affected dogs"but "the EDA transcript in the affected dogs lacked 103 nucleotides encoded by exon 2. We speculate that this exon skipping is caused by a genetic variant located in one of the large introns flanking this exon, which was missed by whole genome sequencing with the illumina short read technology. The altered EDA transcript splicing most likely causes the observed ectodermal dysplasia in the affected dogs. . . . The variant designation for this frame-shifting exon skipping on the transcript level is r.385_487del. The predicted variant on the protein level is p.Met129Valfs*112 and the predicted mutant protein lacks the functionally important collagen-like and TNF-signaling domains" (OMIA variant 1458).
Hadji Rasouliha et al. (2018) reported a single base-pair deletion in the EDA gene (NM_001014770.2:c.842delT; NP_001014770.1:p.Leu281HisfsTer22) as the likely causal variant "in a litter of Dachshund puppies, of which four male puppies showed clinical signs of XLHED" (OMIA variant 1017).
Vasiliadis et al. (2018) independently investigated the same Dachshund family and identified the same variant. Vasiliadis et al. (2018) described the variant as c.458delT as they referred to the ENSEMBL annotation, which lacks the first exon of the EDA gene. A comparison of the ENSEMBL and NCBI annotations of the canine EDA gene is given in Figure S1 of Hadji Rasouliha et al. (2018).
Clinical features: Affected animals are born with symmetrical hairlessness on the forehead and over the dorsal pelvic area. There is often a history of ophthalmia neonatorum (infection behind closed eye lids in neonates). Affected animals have absent or abnormal secondary hairs (Casal et al., 2005, Mauldin et al., 2009). A large number of teeth are missing. Premolars are rarely present and canines, when present, are thinner than normal and pointed outward. Teeth that are present are conically shaped. Most notably molars and incisors, when present, are misshapen and small (Lewis et al., 2010). Signs also include absent sweat glands, decreased tear production, decreased mucociliary clearance in the respiratory tract and symmetrical hypotrichosis. Affected dogs are more susceptible to pulmonary infectious disease than normal dogs. Chronic nasal and ocular discharge are common, as are corneal ulcerations (Casal et al., 2005, Casal et al., 2007, Mauldin et al., 2009).
Pathology: Ectodysplasin A is a key component in ectodermal appendage formation. The gene is transcribed as several splice variants, two of which encode the proteins EDA-A1 and EDA-A2. EDA-A1 binds the receptor EDAR. Anhidrotic ectodermal dysplasia is caused by failure of the ligand-receptor interaction during the development of skin and its appendages, which is necessary for correct development of hair follicles and tooth buds (Kowalczyk et al., 2011, Casal et al., 2005). Histological examination of hairless skin and foot pads shows an absence of hair follicles, adnexal structures, and eccrine glands. Bronchial, tracheal, and esophageal glands are also absent (Casal et al., 1997, Casal et al., 2007, Mauldin et al., 2009). Epidermal hyperpigmentation and orthokeratotic hyperkeratosis are common findings (Moura et al., 2004).
Prevalence: Because the mode of inheritance is X-linked recessive, the condition occurs more often in males.
Control: Breeding of affected animals or known carriers is not recommended.
Genetic testing: There is a test available to detect the causative mutation in the German Shepherd and in Dachshund.
Breeds: Basset Hound, Belgian Shepherd, Bichon Frise, Cocker Spaniel, German Shepherd Dog, Labrador Retriever, Miniature Pinscher, Miniature Poodle, Mixed breed, Pekingese, Whippet, Yorkshire Terrier.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|EDA||ectodysplasin A||Canis lupus familiaris||X||NC_051843.1 (55046702..55482183)||EDA||Homologene, Ensembl, NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|1458||Mixed breed||X-linked hypohidrotic ectodermal dysplasia||EDA||splicing||Naturally occurring variant||CanFam3.1||X||r.385_487del||p.M129fs*112||NM_001014770.2; NP_001014770.1; EDA transcript lacks 103 nucleotides encoded by exon 2, exon skipping is likely to be caused by an intronic splice variant||2016||27449516|
|1017||Dachshund||X-linked hypohidrotic ectodermal dysplasia||EDA||deletion, small (<=20)||Naturally occurring variant||CanFam3.1||X||g.54509504del||c.842delT||p.(L281Hfs*22)||2018||30276836|
|361||German Shepherd Dog||Anhidrotic ectodermal dysplasia||EDA||splicing||Naturally occurring variant||CanFam3.1||X||g.54511433G>A||c.910-1G>A||NM_001014770.2||rs1152388425||2005||16151697||Genomic coordinates in CanFam3.1 und EVA Id provided by Zoe Shmidt and Robert Kuhn.|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2021||Moura, E., Daltro, S.R.T., Sás, D.M., Engracia Filho, J.R., Farias, M.R., Pimpão, C.T. :|
|Challenges in the genetic analysis of a possible case of canine X-linked ectodermal dysplasia. J Small Anim Pract 62:1127-1130, 2021. Pubmed reference: 34076266. DOI: 10.1111/jsap.13385.|
|2020||Moura, E., Henrique Weber, S., Engracia Filho, J.R., Pimpão, C.T. :|
|A hypohidrotic ectodermal dysplasia arising from a new mutation in a Yorkshire Terrier dog. Top Companion Anim Med 39:100404, 2020. Pubmed reference: 32482291. DOI: 10.1016/j.tcam.2020.100404.|
|2019||Moura, E., Rotenberg, I.S., Pimpão, C.T. :|
|X-linked hypohidrotic ectodermal dysplasia-general features and dental abnormalities in affected dogs compared with human dental abnormalities. Top Companion Anim Med 35:11-17, 2019. Pubmed reference: 31122682. DOI: 10.1053/j.tcam.2019.03.002.|
|Vasiliadis, D., Hewicker-Trautwein, M., Klotz, D., Fehr, M., Ruseva, S., Arndt, J., Metzger, J., Distl, O., Vasiliadis, D., Hewicker-Trautwein, M., Klotz, D., Fehr, M., Ruseva, S., Arndt, J., Metzger, J., Distl, O. :|
|A de novo EDA-variant in a litter of shorthaired standard dachshunds with X-linked hypohidrotic ectodermal dysplasia. G3 (Bethesda) 9:95-104, 2019. Pubmed reference: 30397018. DOI: 10.1534/g3.118.200814.|
|2018||Hadji Rasouliha, S., Bauer, A., Dettwiler, M., Welle, M.M., Leeb, T., Hadji Rasouliha, S., Bauer, A., Dettwiler, M., Welle, M.M., Leeb, T. :|
|A frameshift variant in the EDA gene in Dachshunds with X-linked hypohidrotic ectodermal dysplasia. Anim Genet 49:651-654, 2018. Pubmed reference: 30276836. DOI: 10.1111/age.12729.|
|2016||Waluk, D., Zur, G., Kaufmann, R., Welle, M.M., Jagannathan, V., Drögemüller, C., Müller, E.J., Leeb, T., Galichet, A. :|
|A splice defect in the EDA gene in dogs with an X-linked hypohidrotic ectodermal dysplasia (XLHED) phenotype. G3 (Bethesda) 6:2949-2954, 2016. Pubmed reference: 27449516. DOI: 10.1534/g3.116.033225.|
|2013||Shirokova, V., Jussila, M., Hytönen, M.K., Perälä, N., Drögemüller, C., Leeb, T., Lohi, H., Sainio, K., Thesleff, I., Mikkola, M.L. :|
|Expression of Foxi3 is regulated by ectodysplasin in skin appendage placodes. Dev Dyn 242:593-603, 2013. Pubmed reference: 23441037. DOI: 10.1002/dvdy.23952.|
|2011||Kowalczyk, C., Dunkel, N., Willen, L., Casal, M.L., Mauldin, E.A., Gaide, O., Tardivel, A., Badic, G., Etter, A.L., Favre, M., Jefferson, D.M., Headon, D.J., Demotz, S., Schneider, P. :|
|Molecular and therapeutic characterization of anti-ectodysplasin A receptor (EDAR) agonist monoclonal antibodies. J Biol Chem 286:30769-79, 2011. Pubmed reference: 21730053. DOI: 10.1074/jbc.M111.267997.|
|2010||Lewis, JR., Reiter, AM., Mauldin, EA., Casal, ML. :|
|Dental abnormalities associated with X-linked hypohidrotic ectodermal dysplasia in dogs. Orthod Craniofac Res 13:40-7, 2010. Pubmed reference: 20078794. DOI: 10.1111/j.1601-6343.2009.01473.x.|
|2009||Mauldin, E.A., Gaide, O., Schneider, P., Casal, M.L. :|
|Neonatal treatment with recombinant ectodysplasin prevents respiratory disease in dogs with X-linked ectodermal dysplasia. Am J Med Genet A :2045-9, 2009. Pubmed reference: 19533784. DOI: 10.1002/ajmg.a.32916.|
|2007||Casal, ML., Lewis, JR., Mauldin, EA., Tardivel, A., Ingold, K., Favre, M., Paradies, F., Demotz, S., Gaide, O., Schneider, P. :|
|Significant correction of disease after postnatal administration of recombinant ectodysplasin A in canine X-linked ectodermal dysplasia. Am J Hum Genet 81:1050-6, 2007. Pubmed reference: 17924345. DOI: 10.1086/521988.|
|2005||Casal, ML., Scheidt, JL., Rhodes, JL., Henthorn, PS., Werner, P. :|
|Mutation identification in a canine model of X-linked ectodermal dysplasia. Mamm Genome 16:524-31, 2005. Pubmed reference: 16151697. DOI: 10.1007/s00335-004-2463-4.|
|Casal, ML., Mauldin, EA., Ryan, S., Scheidt, JL., Kennedy, J., Moore, PF., Felsburg, PJ. :|
|Frequent respiratory tract infections in the canine model of X-linked ectodermal dysplasia are not caused by an immune deficiency. Vet Immunol Immunopathol 107:95-104, 2005. Pubmed reference: 15946744. DOI: 10.1016/j.vetimm.2005.04.005.|
|2004||Moura, E., Cirio, SM. :|
|Clinical and genetic aspects of X-linked ectodermal dysplasia in the dog -- a review including three new spontaneous cases. Vet Dermatol 15:269-77, 2004. Pubmed reference: 15500478. DOI: 10.1111/j.1365-3164.2004.00407.x.|
|1997||Casal, M.L., Jezyk, P.F., Greek, J.M., Goldschmidt, M.H., Patterson, D.F. :|
|X-linked ectodermal dysplasia in the dog Journal of Heredity 88:513-517, 1997. Pubmed reference: 9419891.|
|1986||Grieshaber, T.L., Blakemore, J.C., Yasulski, S. :|
|Congenital alopecia in a Bichon Frise Journal of the American Veterinary Medical Association 188:1053-1054, 1986. Pubmed reference: 3710892.|
|1985||Chastain, C.B., Swayne, D.E. :|
|Congenital hypotrichosis in male Basset Hound littermates Journal of the American Veterinary Medical Association 187:845-846, 1985. Pubmed reference: 4055508.|
|1984||Kunkle, G.A. :|
|Congenital hypotrichosis in two dogs Journal of the American Veterinary Medical Association 185:84-85, 1984. Pubmed reference: 6746381.|
|1977||Selmanowitz, V.J., Markofsky, J., Orentreich, N. :|
|Heritability of an ectodermal defect. A study of affected dogs. J Dermatol Surg Oncol 3:623-6, 1977. Pubmed reference: 579352. DOI: 10.1111/j.1524-4725.1977.tb00369.x.|
|1970||Selmanowitz, V.J., Kramer, K.M., Orentreich, N., Hyman, A.B. :|
|Congenital ectodermal dysplasia in male miniature poodles Archives of Dermatology 101:613-615, 1970. Pubmed reference: 5462764.|
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