Categories: Integument (skin) phene

Possibly relevant human trait(s) and/or gene(s) (MIM number): 618488 (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: 2014

Species-specific description: Jung et al. (2014) were very careful to note that "Although the phenotype of affected calves strongly resembles BHZD [bovine hereditary zinc deficiency], a zinc deficiency resulting from malabsorption is unlikely to be responsible for the diseased Fleckvieh calves."

Mapping: Having excluded (by sequencing) the SLC39A4 gene, mutations in which cause hereditary zinc deficiency in Holstein-Friesians (see OMIA 000593-9913), Jun et al. (2014) conducted a GWAS on 8 affected calves and 1,339 normal Fleckvieh bulls (each of which had been genotyped with the Illumina BovineHD BeadChip (yielding 644,450 informative SNPs), which mapped this disorder to chromosome BTA21, in "an 18.19 Mb interval from 53,140,245 bp to 71,333,740 bp". Subsequent "Autozygosity mapping within the distal region of BTA 21 revealed a common 1,023 kb segment of extended homozygosity in the eight affected animals (70,550,045 bp – 71,573,501 bp)".

Molecular basis: Analysis of whole-genome sequence data in the candidate region (see Mapping section above), from one affected calf and 42 normal Fleckviehs enabled Jung et al. (2014) "revealed a nonsense mutation (p.W215X) in a phospholipase encoding gene (PLD4) as candidate causal polymorphism". The causality of this mutation was confirmed by sequencing for this mutation in "3,650 animals representing three different breeds". The complete description of the mutation is "c.G645A, p.W215X, BTA 21:71,001,232 bp, rs378824791".

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

Clinical features: As reported by Jun et al. (2014), "Seven calves between the age of seven and 17 weeks with severe skin lesions and poor general health status were admitted to the Clinic of Ruminants. Clinical findings such as scaling and crusting of skin and secondary adhesion of hair were most evident around the muzzle, the eyes, above the sternum and on the extremities . . . . Skin of the inguinal region was seborrhoeic and all palpable lymph nodes were enlarged. The calves suffered from erosions in the interdigital spaces and erosive or ulcerative lesions of the oral mucosa . . . . All animals were underdeveloped in height and weight and had a history of recurring diarrhoea and pneumonia. Two of the calves were supplemented with dietary zinc (750 mg/day), but did not respond to the treatment. Due to the advanced state of the disease and with no prospect for improvement, all animals were euthanized and subjected to necropsy. In hematoxylin and eosin (H&E) stained sections, the skin of the affected animals displayed a mild to severe chronic dermatitis with serocellular crusting and partial superficial bacterial colonization. Multiple intracorneal and intraepidermal accumulations of serum as well as multiple ulcerations and epidermal necroses were present. The epidermis was severely oedematous in multiple sections . . . . Dermis and epidermis were diffusely infiltrated by a moderate to high number of neutrophils. Besides moderate oedema, the dermis exhibited infiltration with lymphocytes and plasma cells to a limited extent. In the cases where the thymus was examined, decreased thymic cellularity and poorly demarcated cortex-medulla-border were observed. Further, the clinical diagnoses of enteritis and pneumonia were confirmed during the pathological examination."

Breed: Simmental (Cattle) (VBO_0000380).
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: