In other species: taurine cattle

Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 131760 (trait) , 131900 (trait) , 601001 (trait) , 131800 (trait) , 131960 (trait) , 609352 (trait) , 148040 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2022

Cross-species summary: Keratins form heterodimers comprising an acidic and a neutral keratin monomer. The two subunits intertwine in-parallel and in-register to give a central rod domain comprising, from the N- to the C-terminus, the 1A-L1-1B-L12-2A-L2-2B subdomains. 1A, 1B, 2A and 2B are coiled-coil subdomains, and L1, L12, L2 are the intervening linkers (Bray et al. 2015).
Keratin 5 (KRT5) heterodimerizes with keratin 14 (KRT14). The KRT5/KRT14 heterodimer forms intermediate filaments required for the integrity of the epidermis. The KRT5 and KRT14 genes are almost exclusively transcribed in the basal layer of the epidermis, but the proteins may persist during keratinocyte differentiation and also be found in higher layers of the epidermis (Coulombe & Lee, 2012).
Variants in KRT5 (or KRT14) may lead to various subtypes of epidermolysis bullosa simplex (EBS). The genotype-phenotype correlation is largely determined by the specific variant. Missense variants and in frame deletions often show a dominant negative effect on heterodimer formation and consequently a dominant mode of inheritance. Variants affecting the highly conserved helical subdomains within the central rod domain result in more severe generalized forms of EBS, while variants affecting the linker domains typically result in milder localized forms of EBS that may be restricted to the palmoplantar epidermis. Nonsense or frameshift variants typically result in autosomal recessive and very severe/lethal forms of EBS (Coulombe & Lee, 2012; Has et al. 2020).

Species-specific name: epidermolysis bullosa simplex, split paw pad disease

History: Kiener et al. (2022) were the first to report KRT5-related epidermolysis bullosa simplex in dogs.

Inheritance: The NP_001332964.1:p.Asn330_Asp335del allele observed in German Shepherd dogs with split paw pad disease most likely shows incomplete penetrance (Rietmann et al. 2024).

Molecular basis: Kiener et al. (2022) "obtained whole genome sequencing data from . . . [an] affected puppy and searched for variants in candidate genes known to cause EB. This revealed a heterozygous missense variant, KRT5:p.(E476K), affecting the highly conserved KLLEGE motif of keratin 5. The mutant allele in the affected puppy arose owing to a de novo mutation event as it was absent from both unaffected parents". This variant affects the rod domain of keratin 5.
Rietmann et al. (2024): "Whole genome sequencing data from an affected [German Shepherd] dog [with split paw pad disease] revealed a private heterozygous 18 bp in frame deletion in the KRT5 gene. The deletion NM_001346035.1:c.988_1005del or NP_001332964.1:p.(Asn330_Asp335del) is predicted to lead to a loss of six amino acids in the L12 linker domain of the encoded keratin 5."

Clinical features: The severity of the clinical phenotype depends on the specific KRT5 variant. Kiener et al. (2022) "examined a Cardigan Welsh Corgi puppy [heterozygous for p.E476K] with skin blistering and erosions that were noticed shortly after birth. It was one of a litter of three puppies, in which both other littermates and the parents were healthy. The affected dog was smaller than the littermates. Vesicles and ulcers were extensively present in the oral cavity, lips and paw pads . . . . Gentle pressure on the skin near affected areas would result in sloughing of the adjacent epidermis (positive Nikolsky sign; ...). The puppy was given supplementary nutrition and adopted by a veterinarian at 10 weeks of age. At that time, the lesions in the oral cavity had healed and the dog was able to eat normally. The dog continued to have waxing and waning lesions on the paw pads, ears, axilla and groin. Blisters would arise intermittently, ulcerate and heal with scarring."
Rietmann et al. (2024) "studied a family of German Shepherd dogs, in which four dogs developed intermittent paw pad lesions and lameness." The clinical phenotype in German Shepherd dogs with the p.Asn330_Asp335del variant was restricted to the paw pad epidermis and less severe than the phenotype in Cardigan Welsh Corgi with the p.E476K variant.

Pathology: Kiener et al. (2022): "At 1 year of age, four skin punch biopsies from lesional areas were obtained under general anesthesia. Histopathologic examination revealed intact subepidermal vesicles along with ulcers, granulation tissue and regions of dermal scarring. Small remnants of basal keratinocytes were evident at the margins of the vesicles and scattered basal keratinocytes were apoptotic. The dog was still alive at 17 months of age (at the time of writing this paper)".
Rietmann et al. (2024): "The paw pads of two of the affected [German Shepherd] dogs [with split paw pad disease] were biopsied and demonstrated cleft formation in the stratum spinosum and stratum corneum, the outermost layers of the epidermis." This finding was unexpected as human patients with KRT5-related EBS show split formation at the basal layer of the epidermis.

Breeds: Cardigan Welsh Corgi (Dog) (VBO_0200290), German Shepherd Dog (Dog) (VBO_0200577).
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: