Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 604536 (trait) , 601975 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0011472: epidermolysis bullosa simplex due to plakophilin deficiency

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2012

Cross-species summary: Renamed from 'Ectodermal dysplasia/skin fragility syndrome' to 'Ectodermal dysplasia/skin fragility syndrome, PKP1-related' [10/06/2024]

Species-specific symbol: ED-SFS

History: The first report of this disorder in animals was in Chesapeake Bay retriever dogs, by Olivry et al. (2012).

Inheritance: The results of a pedigree analysis conducted by Olivry et al. (2012) were "most consistent with an autosomal recessive mode of inheritance".

Molecular basis: Extensive and detailed clinical, histological, electron micrographical and protein immunomapping investigations (the latter showing a lack of plakophilin-1 (PKP1) in affected dogs) by Olivry et al. (2012) suggested a strong candidate gene. Sequencing of the exons and exon-intron junctions of the canine PKP1 gene revealed a causative mutation: "a G-to-C conversion at the IVS1 splice donor site of the first intron . . . , which was homozygous in affected puppies and heterozygous in their parents available for testing. This conversion results in a destruction of the intronic splice donor site resulting in a continual read through to a premature stop codon located nine codons downstream from the mutation . . . . As a consequence, the mutated protein is predicted to be truncated and composed of 75 instead of 749 aminoacids." Using the genetic variant nomenclature of 2015, the causative variant can be decribed as c.202+1G>C. (thanks to Hamutal Mazrier for alerting FN to this discovery)

Clinical features: As reported by Olivry et al. (2012), "In all affected dogs, clinical signs occurred immediately after birth with spontaneous sloughing of the nose and footpad epithelium and bleeding of the ear tips if traumatized. Within 48 hours of birth, the lips and facial superficial skin layers also sloughed when rubbed dry or licked by the mother. Three dogs were kept alive by their breeder for three months; all exhibited waxing and waning superficial skin sloughing with erosions and fissures at areas of friction (axillae, groin, caudal tarsi, footpads), concave ear pinnae and mucocutaneous junctions (nasal planum, philtrum, lips, periocular area)".

Prevalence: This variant has also been detected during routine genetic testing, in Golden Retrievers (Frank Coopman, pers. comm., 2017)

Breeds: Chesapeake Bay Retriever (Dog) (VBO_0200326), Golden Retriever (Dog) (VBO_0200610).
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: