OMIA:000543-9913 : Anhidrotic ectodermal dysplasia, EDA-related in Bos taurus
In other species: dog
Categories: Integument (skin) phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 305100 (trait) , 300451 (gene)
Links to MONDO diseases:
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].
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."
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), Holstein (black and white) (Cattle) (VBO_0000237), Holstein Friesian (Cattle) (VBO_0000239), Japanese Black, Japan (Cattle) (VBO_0004987), Prim'Holstein, France (Cattle) (VBO_0003169), Red Angus-Charolais-Simmental cross, Red Angus-Simmental cross.
|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|
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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|
|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||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)||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*)||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)||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."||2011||21410470||Allele id and p. information were copied from Table 1 of Capuzzello et al. (2022)|
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.
|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||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., Kehler, W., Scholz, H. :|
|Congenital hypotrichosis with anodontia in cattle [German] Praktische Tierarzt 81:496-+, 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.|
|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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