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:

• MONDO:0010585: X-linked hypohidrotic ectodermal dysplasia

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."

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.

Associated gene: