In other species: pig

Categories: Integument (skin) phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 601277 (trait) , 242500 (trait) , 607800 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2008

Mapping: In a pioneering use of tens of thousands of SNP markers ("using either the 25K Affymetrix SNP panel or a custom-made 60K Illumina panel"), Charlier et al. (2008) identified a single 11.78 Mb region on BTA2 in which 3 affected calves were significantly more homozygous for the same allele at each of many SNPs, when compared with 9 normal controls. An investigation of comparative candidate genes in this region identified the ABCA12 gene as a likely culprit. This gene encodes the 12th member of the A subfamily of ATP-binding cassette transporters. Some sequencing of this gene quickly identified the molecular lesion.

Molecular basis: In the words of Charlier et al. (2008): "a missense mutation in exon 39 (A5804G) resulting in an H1935R substitution in the fourth extracellular loop". The His (normal) form of the peptide is conserved in all vertebrates sequenced to date. (FN 080330) Whole-genome sequencing of the affected Shorthorn calf described by O'Rourke et al. (2017), and subsequent checking for deleterious variants in functional candidate genes, enabled Woolley et al. (2019) to identify "a likely causal missense variant on chromosome 2 in the ABCA12 gene (NM_001191294.2:c.6776T>C)". The authors also reported that "Sanger sequencing of the affected calf and the dam confirmed the variant was homozygous in the affected calf and heterozygous in the dam." Eager et al. (2020): "Sanger sequencing of all 53 exons" of the functional candidate gene ABCA12 in an affected still-born Poll Hereford led to the discovery of a likely causal variant, namely a "novel mutation found in exon 34, which was an insertion of a cytosine at position BTA 2:103043495–103043496 or ENSBTAT00000004518.6:c.5689‐5690insC . . . . The frameshift is predicted to result in a premature stop codon at residue 1816, truncating the protein by 781 amino acids – ENSBTAP00000004518.6:p.(Ser1784Ilefs*33)".

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: In the words of Charlier et al. (2008), "Affected calves show cutaneous lesions, with deep fissures separating hyperkeratotic skin plaques and eversion of mucocutaneous junctions (ectropion and eclabium), reminiscent of harlequin ichthyosis in humans".

Prevalence: O'Rourke et al. (2017) reported that "The known mutation (H1935R) in gene ABCA12, responsible for ichthyosis fetalis in Chianina cattle, was shown to be absent in . . . [one Polled Hereford and one Shorthorn affected calf] and their obligate heterozygous parents." Woolley et al. (2019) reported that "genotyping of 130 Shorthorn animals from the same property [as the affected calf described by O'Rourke et al. (2017)] revealed an estimated [c.6776T>C] allele frequency of 3.8%."

Breeds: Chianina (Cattle) (VBO_0000178), Polled Hereford (Cattle) (VBO_0000341), Shorthorn (Cattle) (VBO_0000375).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: