In other species: dog

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: 2005

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).

Molecular basis: In a textbook example of how to make use of clinical information to identify a comparative candidate gene (based on the homologous human disorder) namely KRT5 (keratin 5), Ford et al. (2005) showed that this disorder in the offspring of a Friesian-Jersey bull is due to a 4051G>A base substitution in the bovine KRT5 gene, leading to an E478K amino-acid substitution. The bull turned out to be mosaic for a de novo mutation. Jacinto et al. (2020): "Whole‐genome sequencing [of a "6‐day‐old Belgian Blue‐Holstein calf . . . [with] a syndrome resembling epidermolysis bullosa simplex"] revealed a heterozygous disruptive in‐frame deletion variant in KRT5 (c.534_536delCAA). Genotyping of both parents confirmed the variant as de novo mutation."

Breeds: Belgian Blue (Cattle) (VBO_0000139), Friesian cross (Cattle) (VBO_0016846).
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: