GJB6 missense variant in a Labrador Retriever with paw pad hyperkeratosis

Palmoplantar keratoderma in humans is a condition defined by an abnormally thickened cornified skin layer on the hands and feet. In animals, the corresponding disease is commonly termed paw pad hyperkeratosis. It can be acquired due to repeated trauma, infections, cancer, or inflammatory dermatoses, or inherited due to pathogenic variants in genes involved in skin development. More than 60 different genes involved in the development of palmoplantar keratoderma have been described. Here, we investigated a female Labrador Retriever showing hyperkeratosis on all four paw pads and most digital pads. Histologically, the stratum corneum was expanded by predominantly orthokeratotic hyperkeratosis with occasional mild parakeratotic areas. DNA of the affected dog was isolated from EDTA-blood and whole genome sequencing was performed. Comparison of the whole genome sequencing data to 1664 unaffected control dogs revealed a private de novo heterozygous missense variant in the GJB6 gene which was not present in the parents. GJB6 encodes connexin 30, a subunit of the desmosome. In humans, pathogenic variants in this gene cause isolated deafness or Clouston syndrome, an autosomal dominant condition that is characterized by alopecia, nail dystrophy, and palmoplantar hyperkeratosis. The paw pad hyperkeratosis phenotype in the investigated dog shows similarities to Clouston syndrome and strongly suggests that the GJB6 missense variant is responsible for its condition. However, our investigation also highlights differences between human and dog that could provide deeper insights into the function of GJB6.