Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 605623 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2018

Cross-species summary: Renamed from 'Acrodermatitis, lethal' to 'Acrodermatitis, lethal, MKLN1-related' [11/06/2024]

Species-specific name: Lethal acrodermatitis

Species-specific symbol: LAD

Mapping: "Utilizing a combination of genome wide association study and haplotype analysis," Bauer et al. (2018) "mapped the LAD locus to a critical interval of ~1.11 Mb on chromosome 14."

Molecular basis: Baurer et al. (2018) reported that "Whole genome sequencing of an LAD affected dog revealed a splice region variant in the MKLN1 gene that was not present in 191 control genomes (chr14:5,731,405T>G or MKLN1:c.400+3A>C). This variant showed perfect association in a larger combined Bull Terrier/Miniature Bull Terrier cohort of 46 cases and 294 controls. The variant was absent from 462 genetically diverse control dogs of 62 other dog breeds. RT-PCR analysis of skin RNA from an affected and a control dog demonstrated skipping of exon 4 in the MKLN1 transcripts of the LAD affected dog, which leads to a shift in the MKLN1 reading frame."

Clinical features: "Affected puppies show characteristic skin lesions on the feet and on the face, diarrhea, bronchopneumonia, and a failure to thrive. The skin lesions consist of erythema and tightly adherent scales, erosions or ulcerations with crusts involving primarily the feet, distal limbs, elbows, hocks, and muzzle. Later on, hyperkeratosis of the footpads and deformation of the nails occur. LAD affected dogs also show a coat color dilution in pigmented skin areas. An abnormally arched hard palate impacted with decayed, malodorous food is a characteristic clinical marker for the disease (Jezyk et al. 1986; McEwan, 1990; McEwan et al. 2000). LAD dogs are immunodeficient with a reduction in serum IgA levels and frequently suffer from skin infections with Malassezia or Candida (McEwan et al. 2001; McEwan et al. 2003). Affected puppies typically die before they reach an age of two years, either due to infections such as bronchopneumonia or because they are euthanized when their paw pad lesions become very severe and painful. They grow slower than their non-affected littermates and at the age of one year have about half the body weight and size of an unaffected dog (McEwan et al. 2000)." [This summary was copied from Bauer et al. 2018] Although the clinical signs resemble zinc deficiency, it is not clear at all whether the disease has any relation to zinc metabolism (Bauer et al. 2018). Oral supplementation with zinc or intravenous zinc injections did not improve the condition (Jezyk et al. 1986).

Breeds: Bull Terrier (Dog) (VBO_0200255), Miniature Bull Terrier (Dog) (VBO_0200882).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: