OMIA:002081-9615 : Epidermolysis bullosa simplex, KRT5-related in Canis lupus familiaris (dog)

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)

Single-gene 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:

Symbol Description Species Chr Location OMIA gene details page Other Links
KRT5 keratin 5, type II Canis lupus familiaris 27 NC_051831.1 (2565565..2571930) KRT5 Homologene, Ensembl , NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
1480 Cardigan Welsh Corgi (Dog) Epidermolysis bullosa, simplex, KRT5-related KRT5 missense Naturally occurring variant UU_Cfam_GSD_1.0 27 g.44080887C>T c.1426G>A p.(E476K) NM_001346035.1; NP_001332964.1 2022 36004757
1697 German Shepherd Dog (Dog) Epidermolysis bullosa simplex, localized, KRT5-related KRT5 delins, small (<=20) Naturally occurring variant UU_Cfam_GSD_1.0 27 NC_049248.1:g.44081942_44091959del NM_001346035.1:c.988_1005del NP_001332964.1:p.(N330_D335del) 2024 38742646

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2024). OMIA:002081-9615: Online Mendelian Inheritance in Animals (OMIA) [dataset]. https://omia.org/. https://doi.org/10.25910/2AMR-PV70

References

Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.

2024 Rietmann, S.J., Lange, A., Soto, S., Thom, N., Manz, E., Jagannathan, V., Mayer, U., Leeb, T. :
KRT5 in-frame deletion in a family of German Shepherd dogs with split paw pad disease resembling localized epidermolysis bullosa simplex in human patients. Anim Genet 55:692-696, 2024. Pubmed reference: 38742646. DOI: 10.1111/age.13444.
2022 Kiener, S., Mauldin, E.A., Jagannathan, V., Casal, M.L., Leeb, T. :
KRT5 missense variant in a Cardigan Welsh Corgi with epidermolysis bullosa simplex. Anim Genet 53:892-896, 2022. Pubmed reference: 36004757. DOI: 10.1111/age.13257.
2020 Has, C., Bauer, J.W., Bodemer, C., Bolling, M.C., Bruckner-Tuderman, L., Diem, A., Fine, J.D., Heagerty, A., Hovnanian, A., Marinkovich, M.P., Martinez, A.E., McGrath, J.A., Moss, C., Murrell, D.F., Palisson, F., Schwieger-Briel, A., Sprecher, E., Tamai, K., Uitto, J., Woodley, D.T., Zambruno, G., Mellerio, J.E. :
Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. Br J Dermatol 183:614-627, 2020. Pubmed reference: 32017015. DOI: 10.1111/bjd.18921.
2015 Bray, D.J., Walsh, T.R., Noro, M.G., Notman, R. :
Complete structure of an epithelial keratin dimer: Implications for intermediate filament assembly. PLoS One 10:e0132706, 2015. Pubmed reference: 26181054. DOI: 10.1371/journal.pone.0132706.
2012 Coulombe, P.A., Lee, C.H. :
Defining keratin protein function in skin epithelia: epidermolysis bullosa simplex and its aftermath. J Invest Dermatol 132:763-75, 2012. Pubmed reference: 22277943. DOI: 10.1038/jid.2011.450.

Edit History


  • Created by Frank Nicholas on 27 Aug 2022
  • Changed by Frank Nicholas on 27 Aug 2022
  • Changed by Imke Tammen2 on 08 Sep 2022
  • Changed by Imke Tammen2 on 17 May 2024
  • Changed by Tosso Leeb on 17 May 2024
  • Changed by Tosso Leeb on 18 May 2024