OMIA:000543-9913 : Anhidrotic ectodermal dysplasia, EDA-related in Bos taurus (taurine cattle)

In other species: dog

Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 305100 (trait) , 300451 (gene)

Links to relevant human diseases in MONDO:

Mendelian trait/disorder: yes

Mode of inheritance: X-linked

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2001

Species-specific name: Congenital hypotrichosis and anodontia defect; Ectodermal dysplasia; X-linked hypohidrotic ectodermal dysplasia-1

Species-specific symbol: HAD; HED; XLHED; ECTD1

Species-specific description: Because of the obvious homology of this disorder with the homologous human disorder, Drögemüller et al. (2001) proposed that the bovine disorder be called by the name of its human homologue, which is now done in this catalogue. The earlier names are listed here as species-specific names [Frank Nicholas 20 June 2002].

Mapping: Xq22

Markers: Braun et al. 1988) reported a "Simmenthal/Red Holstein cross-breed" calf with evidence of "anhidrotic ectodermal dysplasia" and with " a chromosomal anomaly (Xq-deletion)".

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Drögemüller et al. (2001) demonstrated that this bovine disorder is due to a large deletion including exon 3 in the gene for ectodysplasin (ED1; now called EDA), in black-and-white German Holstein cattle. The following year, a different mutation was discovered in red-and-white German Holstein cattle: "a single G >T transversion was located at the second position of intron 8 (IVS8 +2T>G). The mutation changed the canonical GT dinucleotide at the beginning of the 5′ splice site sequence into GG" (Drögemüller et al., 2002). Drögemüller et al. (2006) reported a nonsense mutation (p.R244X) as a likely causal variant in an affected Red Angus-Charolais-Simmental cross, whose clinical signs were reported by Barlund et al. (2007). Ogino et al. (2011) reported yet another EDA mutation: "a 19 bp deletion in exon 1 in male Holstein calves". Yet another mutation was reported by Karlskov-Mortensen et al. (2011) in Danish Red Holstein cattle, namely "a LINE1-derived pseudoexon between EDA exons 1 and 2. The 161-bp-long pseudoexon introduces a shift in reading frame and a premature stop codon early in EDA exon 2". A sixth likely causal variant was report by Gargani et al. (2011): "a single nucleotide polymorphism (SNP) G/A at the 9th base of exon 8 [GenBank: AJ278907.1 position 30.549]" in two affected Holstein-Friesian males. The authors also reported that "This SNP is located in the exonic splicing enhancer (ESEs) recognized by SRp40 protein. As a consequence, the spliceosome machinery is no longer able to recognize the sequence as exonic and causes exon skipping. The mutation determines the deletion of the entire exon (131 bp) in the RNA processing, causing a severe alteration of the protein structure and thus the disease." A seventh mutation was reported by Ogino et al. (2012), this time in Japanese Black cattle: "an insertion of 4 bp at nucleotide 280 (c.280_281insAGGG) in exon 1. This insertion is predicted to result in a frameshift beginning with amino acid residue 94, with a termination codon occurring at position 143 (p.Gly94GlufsX49), compared to the normal bovine ectodysplasin A protein sequence of 391 amino acids". Escouflaire et al. (2019) reported a most interesting new likely causal variant that appears to have arisen de novo in a female French Holstein, namely "a 3.8-Mb inversion on chromosome X of a heterozygous female calf that causes a dominant and generalized form of HED via skewed X-inactivation and truncation of the EDA protein." The breakpoints are "located in the first intron of EDA and the first intron of XIST" [the latter being the gene that initiates X-inactivation]. As the authors explain, the inversion "leads to the separation of the XIST exon 1 from the rest of the gene. Thus, if transcribed, the mutant XIST RNA would lack the main evolutionary constrained element among mammals, and contain only 48% of the normal transcript. In addition, this mutation does not affect the integrity of TSIX, which encodes the main repressor of XIST. . . . Although we could not conduct expression studies to validate our hypothesis, these arguments combined with the observation of a generalized HED phenotype in a female heterozygous for a mutation that truncates EDA, suggest that XCI is impaired on the X chromosome carrying the mutation and results in the skewed inactivation of the normal X." O'Toole et al. (2021): "Whole-genome sequencing (WGS) identified a 53 kb deletion of the X chromosome including parts of the EDA gene as well as the entire AWAT2 gene" as the likely causal variant for a form of hypohidrotic ectodermal dysplasia reported in five "Red Angus-Simmental bull calves born over a 6-year period (2013–2019) in a single herd in the Western United States". By comparing whole-genome sequence from a 45-day-old male British Blue crossbred calf showing a phenotype consistent with hypohidrotic ectodermal dysplasia, with many thousands of other bovine genome sequences, Capuzzello et al. (2022) identified "a 21,899 base-pair deletion encompassing the coding exon 2 of EDA [a functional candidate gene], predicted to result in an altered transcript and aberrant protein" for which the affected calf was hemizygous. The authors "hypothesized that this deletion occurred de novo or was inherited from a heterozygous dam. Unfortunately, no samples from the parents were available to test these two possibilities." Krull et al. (2024) identified a "single missense variant (rs439722471) at position X:g.80411716T>C (ARS-UCD1.3) [p.Glu294Gly]" as the likely causative variant for X-linked hypohidrotic ectodermal dysplasia in Limousin cattle. The variant was not present in 7132 control animals.
Reinartz et al. (2024) "identified a three-generation family of Fleckvieh cattle with male calves exhibiting clinical and histopathological signs consistent with an X-linked recessive HAD (XHED). Whole genome and Sanger sequencing of cDNA showed a perfect association of the missense mutation g.85716041G>A (ss2019497443, rs1114816375) within the EDA gene with all three cases following an X-linked recessive inheritance, but normal EDAR and EDARADD. ... incisors and canines were more severely affected in one of the calves, which correlated with the presence of a homozygous missense mutation of RNF111 (g.51306765T>G), a putative candidate gene possibly associated with tooth number in EDA-deficient Fleckvieh calves."

Clinical features: Capuzzello et al. (2022): "Hypotrichosis, oligodontia, bronchopneumonia, an umbilical abscess, and a subcutaneous abscess of approximately 1 cm on the medial aspect of the right fore fetlock were all confirmed by gross inspection postmortem. In addition to the complete absence of incisors, only one, partially erupted, abnormally shaped cheek tooth was present at the caudal aspect of each maxillary arcade . . . . On sectioning of the mandible at the angle of the ramus bilaterally, one abnormally shaped unerupted tooth was also present at the caudal aspect of each arcade. Lesions typical of chronic bronchopneumonia were found: multifocal fibrous pleural adhesions and pulmonary consolidation cranioventrally with small amounts of mucoid to suppurative material in airways."

Pathology: Capuzzello et al. (2022): "Histopathological examination of haired skin revealed that in comparison with the control calf, in the skin samples of the affected calf (more pronounced in the biopsy from an area with marked alopecia and mildly in another skin area with erosion), the number of hair follicles was lower, with smaller follicular size and a predominance of telogen-phase hairs . . . . Apocrine and sebaceous glands were present in all examined skin sections from the affected calf. Although no attempt was made to quantify the density of structures, the apocrine glands appeared to be similar in number and size when compared with the control calf, and the number of sebaceous glands in the affected calf appeared to be similar in sections from both calves. In the area with prominent alopecia, the sebaceous glands seemed smaller in size but they look fully developed in the area with erosion. Multifocal epidermal erosions, and ulceration with attendant mild mixed inflammation and serocellular crust formation and epidermal hyperplasia were also noted. Nasolabial glands and ducts were not observed in the nasal planum sample of the affected calf. Bronchial glands were likewise not clearly visible in the limited number of lung sections examined against a background of inflammation. Marked fibrinous, chronic-active bronchointerstitial pneumonia with multifocal necrotising bronchiolitis, bronchiolar hyperplasia, bronchiolitis obliterans, alveolar multinucleate cells, and patchy type II pneumocyte hyperplasia were noted in samples from the cranial lobes bilaterally."

Breeds: British Blue x Holstein-Friesian cross, Danish Holstein (Cattle) (VBO_0000190), Deutsche Holstein Schwarzbunt, Germany (Cattle) (VBO_0003152), Fleckvieh-Simmental, Germany (Cattle) (VBO_0002354), Holstein (black and white) (Cattle) (VBO_0000237), Holstein Friesian (Cattle) (VBO_0000239), Japanese Black, Japan (Cattle) (VBO_0004987), Limousin (Cattle) (VBO_0000274), Prim'Holstein, France (Cattle) (VBO_0003169), Red Angus-Charolais-Simmental cross, Red Angus-Simmental cross.
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
EDA ectodysplasin A Bos taurus X NC_037357.1 (80803385..80405885) EDA Homologene, Ensembl , NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

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 Year Published PubMed ID(s) Acknowledgements
711 Danish Holstein (Cattle) Anhidrotic ectodermal dysplasia EDA HED6 insertion, gross (>20) Naturally occurring variant X "a LINE1-derived pseudoexon between EDA exons 1 and 2. The 161-bp-long pseudoexon introduces a shift in reading frame and a premature stop codon early in EDA exon 2" 2011 22034998 Allele id was copied from Table 1 of Capuzzello et al. (2022)
645 Deutsche Holstein Schwarzbunt, Germany (Cattle) Anhidrotic ectodermal dysplasia EDA HED1 deletion, gross (>20) Naturally occurring variant X c.397_502del p.(M133Vfs*111) a large deletion including exon 3 in the gene for ectodysplasin (ED1; now called EDA) 200922: g. info moved to here (g.85821470) until it can be standardised 2001 11591646 Variant information kindly provided or confirmed by Hubert Pausch, including information from Additional Table 6 of Jansen et al. (2013) BMC Genomics201314:446 https://doi.org/10.1186/1471-2164-14-446 Allele id and p. information were copied from Table 1 of Capuzzello et al. (2022)
1120 Prim'Holstein, France (Cattle) Generalized hypohidrotic ectodermal dysplasia EDA HED8 inversion Naturally occurring variant ARS-UCD1.2 X g.77174882_80737442inv Escouflaire et al. (2019): The "first breakpoint . . . [is] between positions 82,271,052 and 82,271,053 bp on chromosome X . . . The second breakpoint is situated at position 86,034,441 bp within the EDA intron 1" 2019 31533624 Allele id was copied from Table 1 of Capuzzello et al. (2022).
1293 Red Angus-Simmental cross Hypohidrotic ectodermal dysplasia EDA HED9 deletion, gross (>20) Naturally occurring variant ARS-UCD1.2 X g.80382423_80435202del GCF_002263795.1 (O'Toole et al., 2021) 2021 33801223 Allele id was copied from Table 1 of Capuzzello et al. (2022).
373 Deutsche Holstein Schwarzbunt, Germany (Cattle) Anhidrotic ectodermal dysplasia EDA HED2 splicing Naturally occurring variant ARS-UCD1.2 X g.80411671A>C c.924+2T>G c.DNA position is based on NM_001081743.2 rs5334474632 2002 12021844 The genomic location on ARS-UCD1.2 was determined by Katie Eager and Shernae Woolley, EMAI, NSW. Department of Primary Industries. Allele id was copied from Table 1 of Capuzzello et al. (2022)
1295 Holstein Friesian (Cattle) Anhidrotic ectodermal dysplasia EDA HED5 splicing Naturally occurring variant ARS-UCD1.2 X g.80411795C>A c.802C>A "a single nucleotide polymorphism (SNP) G/A at the 9th base of exon 8 [GenBank: AJ278907.1 position 30.549] ... Sequencing of the RT-PCR products revealed that the amplified fragment of the affected animals lacked ... exon 8. At the protein level, the exon skipping leads to a frameshift and consequently to a premature stop codon." (Gargani et al., 2011) rs5334475058 2011 21740563 Allele id and c. information were copied from Table 1 of Capuzzello et al. (2022)
1294 Red Angus-Charolais-Simmental cross Anhidrotic ectodermal dysplasia EDA HED3 nonsense (stop-gain) Naturally occurring variant ARS-UCD1.2 X g.80415626G>A c.730C>T p.(R244*) rs5334474792 2007 17616058 Reference not in PubMed; see OMIA 000543-9913 for reference details The g. coordinate for the named reference genome assembly, together with the c. coordinate, were kindly provided by Tosso Leeb (22 March 2021). Allele id was copied from Table 1 of Capuzzello et al. (2022).
1484 British Blue x Holstein-Friesian cross Anhidrotic ectodermal dysplasia, EDA-related EDA HED10 deletion, gross (>20) Naturally occurring variant ARS-UCD1.2 X g.80516615_80538514del c.397_502del p.(M133Vfs*111) NM_001081743.2; NP_001075212.1 2022 36068608 Allele id was copied from Table 1 of Capuzzello et al. (2022).
586 Japanese Black, Japan (Cattle) Anhidrotic ectodermal dysplasia EDA HED7 insertion, small (<=20) Naturally occurring variant ARS-UCD1.2 X g.80802800_80802801insCCCT c.280_281insAGGG p.(G94Qfs*49) rs5334475024 2012 22497423 The genomic location on ARS-UCD1.2 was determined by Katie Eager and Shernae Woolley, EMAI, NSW. Department of Primary Industries. Allele id was copied from Table 1 of Capuzzello et al. (2022).
482 Holstein (black and white) (Cattle) Anhidrotic ectodermal dysplasia EDA HED4 deletion, small (<=20) Naturally occurring variant ARS-UCD1.2 X g.80803015_80803033del c.48_66del p.(A16S22fs*55) "a 19-bp deletion at nucleotides c.48_66 in exon 1 ... . This mutation is predicted to generate a truncated 49 aa protein." rs5334474984 2011 21410470 Allele id and p. information were copied from Table 1 of Capuzzello et al. (2022)
1661 Limousin (Cattle) Hypohidrotic ectodermal dysplasia, X-linked EDA HED11 missense Naturally occurring variant ARS-UCD1.3 X g.80411716T>C c.881A>G p.(E294G) NM_001081743.2; NP_001075212.1 rs439722471 2024 38252617
1665 Fleckvieh-Simmental, Germany (Cattle) Hypohidrotic ectodermal dysplasia, X-linked EDA missense Naturally occurring variant ARS-UCD1.3 X g.80417567C>T c.679G>A p.(G227R) NM_001081743.2; NP_001075212.1; published as g.85716041G>A in ARS-UCD2.0 rs1114816375 2023 38275590

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2024). OMIA:000543-9913: Online Mendelian Inheritance in Animals (OMIA) [dataset]. https://omia.org/. https://doi.org/10.25910/2AMR-PV70

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.

2024 Krull, F., Bleyer, M., Schäfer, J., Brenig, B. :
A missense mutation in the highly conserved TNF-like domain of Ectodysplasin A is the candidate causative variant for X-linked hypohidrotic ectodermal dysplasia in Limousin cattle: Clinical, histological, and molecular analyses. PLoS One 19:e0291411, 2024. Pubmed reference: 38252617. DOI: 10.1371/journal.pone.0291411.
2023 Reinartz, S., Weiß, C., Heppelmann, M., Hewicker-Trautwein, M., Hellige, M., Willen, L., Feige, K., Schneider, P., Distl, O. :
A missense mutation in the collagen triple helix of EDA is associated with X-linked recessive hypohidrotic ectodermal dysplasia in Fleckvieh cattle. Genes (Basel) 15:8, 2023. Pubmed reference: 38275590. DOI: 10.3390/genes15010008.
2022 Capuzzello, G., Jacinto, J.G.P., Häfliger, I.M., Chapman, G.E., Martin, S.S., Viora, L., Jonsson, N.N., Drögemüller, C. :
A large deletion encompassing exon 2 of the ectodysplasin A (EDA) gene in a British blue crossbred calf with hypohidrotic ectodermal dysplasia. Acta Vet Scand 64:23, 2022. Pubmed reference: 36068608. DOI: 10.1186/s13028-022-00641-2.
2021 O'Toole, D., Häfliger, I.M., Leuthard, F., Schumaker, B., Steadman, L., Murphy, B., Drögemüller, C., Leeb, T. :
X-linked hypohidrotic ectodermal dysplasia in crossbred beef cattle due to a large deletion in EDA. Animals (Basel) 11:657, 2021. Pubmed reference: 33801223. DOI: 10.3390/ani11030657.
2019 Escouflaire, C., Rebours, E., Charles, M., Orellana, S., Cano, M., Rivière, J., Grohs, C., Hayes, H., Capitan, A. :
Α de novo 3.8-Mb inversion affecting the EDA and XIST genes in a heterozygous female calf with generalized hypohidrotic ectodermal dysplasia. BMC Genomics 20:715, 2019. Pubmed reference: 31533624. DOI: 10.1186/s12864-019-6087-1.
2012 Ogino, A., Shimizu, K., Tanabe, Y., Morita, M. :
De novo mutation of the bovine EDA gene associated with anhidrotic ectodermal dysplasia in Japanese Black cattle. Anim Genet 43:646, 2012. Pubmed reference: 22497423. DOI: 10.1111/j.1365-2052.2011.02290.x.
2011 Gargani, M., Valentini, A., Pariset, L. :
A novel point mutation within the EDA gene causes an exon dropping in mature RNA in Holstein Friesian cattle breed affected by X-linked anhidrotic ectodermal dysplasia. BMC Vet Res 7:35, 2011. Pubmed reference: 21740563. DOI: 10.1186/1746-6148-7-35.
Karlskov-Mortensen, P., Cirera, S., Nielsen, O.L., Arnbjerg, J., Reibel, J., Fredholm, M., Agerholm, J.S. :
Exonization of a LINE1 fragment implicated in X-linked hypohidrotic ectodermal dysplasia in cattle. Anim Genet 42:578-584, 2011. Pubmed reference: 22034998. DOI: 10.1111/j.1365-2052.2011.02192.x.
Ogino, A., Kohama, N., Ishikawa, S., Tomita, K., Nonaka, S., Shimizu, K., Tanabe, Y., Okawa, H., Morita, M. :
A novel mutation of the bovine EDA gene associated with anhidrotic ectodermal dysplasia in Holstein cattle. Hereditas 148:46-9, 2011. Pubmed reference: 21410470. DOI: 10.1111/j.1601-5223.2010.02202.x.
2007 Barlund, C.S., Clark, E.G., Leeb, T., Drögemüller, C., Palmer, C.W. :
Congenital hypotrichosis and partial anodontia in a crossbred beef calf. Can Vet J 48:612-4, 2007. Pubmed reference: 17616058.
2006 Drögemüller, C., Barlund, C.S., Palmer, C.W., Leeb, T. :
A novel mutation in the bovine EDA gene causing anhidrotic ectodermal dysplasia (Brief report) Archiv fur Tierzucht 49:615-616, 2006. DOI: 10.5194/aab-49-615-2006.
2005 Seeliger, F., Drögemüller, C., Tegtmeier, P., Baumgartner, W., Distl, O., Leeb, T. :
Ectodysplasin-1 deficiency in a German Holstein bull associated with loss of respiratory mucous glands and chronic rhinotracheitis. J Comp Pathol 132:346-9, 2005. Pubmed reference: 15893993. DOI: 10.1016/j.jcpa.2004.11.001.
2003 Drogemuller, C., Distl, O., Leeb, T. :
X-linked anhidrotic ectodermal dysplasia (ED1) in men, mice, and cattle Genetics Selection Evolution 35:S137-45, 2003. Pubmed reference: 12927086. DOI: 10.1051/gse:2003022.
2002 Drögemüller, C., Kuiper, H., Peters, M., Guionaud, S., Distl, O., Leeb, T. :
Congenital hypotrichosis with anodontia in cattle: a genetic, clinical and histological analysis. Vet Dermatol 13:307-13, 2002. Pubmed reference: 12464063.
Drögemüller, C., Peters, M., Pohlenz, J., Distl, O., Leeb, T. :
A single point mutation within the ED1 gene disrupts correct splicing at two different splice sites and leads to anhidrotic ectodermal dysplasia in cattle. J Mol Med 80:319-23, 2002. Pubmed reference: 12021844. DOI: 10.1007/s00109-002-0320-z.
2001 Drögemüller, C., Distl, O., Leeb, T. :
Partial deletion of the bovine ED1 gene causes anhidrotic ectodermal dysplasia in cattle Genome Research 11:1699-1705, 2001. Pubmed reference: 11591646. DOI: 10.1101/gr.182501.
Kuiper, H., Kutschke, L., Drogemuller, C., Leeb, T., Distl, O. :
Assignment of the bovine ectodysplasin A gene (ED1) to bovine Xq22 -> q24 by fluorescence in situ hybridization Cytogenetics & Cell Genetics 92:356-357, 2001.
2000 Distl, O., Drogemuller, C., Kuiper, H., Kutschke, L., Hermanns, W., Kehler, W., Scholz, H. :
Genetic studies of congenital hypotrichosis with anodontia in German Holstein calves [German] Tierarztliche Umschau 55:72-+, 2000.
Distl, O., Drogemuller, C., Kuiper, H., Kutschke, L., Kehler, W., Scholz, H. :
Congenital hypotrichosis with anodontia in cattle [German] Praktische Tierarzt 81:496-+, 2000.
Drogemuller, C., Neander, S., Klippert, H., Kuiper, H., Kutschke, L., Guionaud, S., Ueberschar, S., Scholz, H., Distl, O. :
Genetic analysis of congenital hypotrichosis with anodontia in cattle [German] Archiv fur Tierzucht-Archives of Animal Breeding 43:213-222, 2000.
1988 Braun, U., Ansari, H.A., Hediger, R., Süss, U., Ehrensperger, F. :
[Hypotrichosis and oligodontia, combined with an Xq-deletion, in a calf of the Swiss Holstein breed]. Tierarztl Prax 16:39-44, 1988. Pubmed reference: 3368908.
Wijeratne, W.V.S., O'Toole, D., Wood, L., Harkness, J.W. :
A genetic, pathological and virological study of congenital hypotrichosis and incisor anodontia in cattle Veterinary Record 122:149-152, 1988. Pubmed reference: 2836985.
1971 Selmanowitz, V.J. :
Ectodermal dysplasia in cattle : Analogues in man British Journal of Dermatology 84:258-265, 1971. Pubmed reference: 4929446.

Edit History


  • Created by Frank Nicholas on 22 Mar 2011
  • Changed by Frank Nicholas on 17 Sep 2011
  • Changed by Frank Nicholas on 06 Dec 2011
  • Changed by Frank Nicholas on 09 Dec 2011
  • Changed by Frank Nicholas on 14 Jun 2012
  • Changed by Frank Nicholas on 18 Sep 2012
  • Changed by Frank Nicholas on 08 Aug 2017
  • Changed by Frank Nicholas on 23 Sep 2019
  • Changed by Frank Nicholas on 19 Mar 2021
  • Changed by Frank Nicholas on 20 Mar 2021
  • Changed by Frank Nicholas on 09 Sep 2022
  • Changed by Imke Tammen2 on 24 Jan 2024
  • Changed by Imke Tammen2 on 07 Feb 2024