OMIA 000543-9913 : Anhidrotic ectodermal dysplasia, EDA-related in Bos taurus

In other species: dog

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

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".

Breeds: Holstein, Japanese Black.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
EDA ectodysplasin A Bos taurus X NC_037357.1 (80803322..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.

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
Holstein Anhidrotic ectodermal dysplasia EDA deletion, small (<=20) X "a 19 bp deletion in exon 1" 2011 21410470
Danish Holstein Anhidrotic ectodermal dysplasia EDA insertion, gross (>20) 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
Holstein Friesian Anhidrotic ectodermal dysplasia EDA splicing X "a single nucleotide polymorphism (SNP) G/A at the 9th base of exon 8 [GenBank: AJ278907.1 position 30.549]" (Gargani et al., 2011) 2011 21740563
Japanese Black Anhidrotic ectodermal dysplasia EDA insertion, small (<=20) X c.280_281insAGGG 2012 22497423
Red Angus-Simmental cross Hypohidrotic ectodermal dysplasia EDA deletion, gross (>20) ARS-UCD1.2 X 80,382,423_80,435,202del52,780 GCF_002263795.1 (O'Toole et al., 2021) 2021 33801223
Red Angus-Charolais-Simmental cross Anhidrotic ectodermal dysplasia EDA nonsense (stop-gain) ARS-UCD1.2 X g.80415626G>A c.730C>T p.R244X 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)
German Holstein Anhidrotic ectodermal dysplasia EDA deletion, gross (>20) UMD3.1 X c.397_502del 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
French Holstein Generalized hypohidrotic ectodermal dysplasia EDA inversion UMD3.1 X g.82271053_86034441inv 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
German Holstein Anhidrotic ectodermal dysplasia EDA splicing UMD3.1 X g.85710147G>T c.924+2G>T IVS8 +2T>G 2002 12021844 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

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.
2021 O'Toole et al. :
X-Linked hypohidrotic ectodermal dysplasia in crossbred beef cattle due to a large deletion in EDA Animals 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 Drogemuller, 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.
Drogemuller, 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 Drogemuller, 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.

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