OMIA 000543-9615 : Anhidrotic ectodermal dysplasia, EDA-related in Canis lupus familiaris

In other species: cattle

Possibly relevant human trait(s) and/or gene(s) (MIM number): 305100

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

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 (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).

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 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.

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".

Rasouliha et al. (2018) reported a single base-pair deletion in the EDA gene (c.842delT; p.Leu281HisfsTer22) as the likely causal variant "in a litter of Dachshund puppies, of which four male puppies showed clinical signs of XLHED"

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.

Breeds: Basset Hound, Belgian Shepherd, bichon frise, Cocker Spaniel, German Shepherd Dog, Labrador Retriever, Miniature Pinscher, Miniature Poodle, Pekingese, Whippet.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
EDA ectodysplasin A Canis lupus familiaris X NC_006621.3 (54078694..54515535) EDA Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective.

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
German Shepherd Dog Anhidrotic ectodermal dysplasia EDA splicing c.910-1G>A 2005 16151697
Dachshund X-linked hypohidrotic ectodermal dysplasia EDA deletion, small (<=20) CanFam 3.1 X g.54509504delT c.842delT p.Leu281HisfsTer22 2018 30276836

References


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.
2018 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 :, 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) :, 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., 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.
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.
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. :
Heretibality of an ectodermal defect: a study of affected dogs Journal of Dermatology and Surgical Oncology 3:623-626, 1977.
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.

Edit History


  • Created by Frank Nicholas on 05 Aug 2011
  • Changed by Martha MaloneyHuss on 02 Sep 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 21 Oct 2012
  • Changed by Tosso Leeb on 23 Dec 2015
  • Changed by Frank Nicholas on 04 Aug 2016
  • Changed by Frank Nicholas on 11 Oct 2018