Abstract
In humans, congenital and hereditary skin diseases associated with epidermal cell-cell separation (acantholysis) are very rare, and spontaneous animal models of these diseases are exceptional. Our objectives are to report a novel congenital acantholytic dermatosis that developed in Chesapeake Bay retriever dogs. Nine affected puppies in four different litters were born to eight closely related clinically normal dogs. The disease transmission was consistent with an autosomal recessive mode of inheritance. Clinical signs occurred immediately after birth with superficial epidermal layers sloughing upon pressure. At three month of age, dogs exhibited recurrent superficial skin sloughing and erosions at areas of friction and mucocutaneous junctions; their coat was also finer than normal and there were patches of partial hair loss. At birth, histopathology revealed severe suprabasal acantholysis, which became less severe with ageing. Electron microscopy demonstrated a reduced number of partially formed desmosomes with detached and aggregated keratin intermediate filaments. Immunostaining for desmosomal adhesion molecules revealed a complete lack of staining for plakophilin-1 and anomalies in the distribution of desmoplakin and keratins 10 and 14. Sequencing revealed a homozygous splice donor site mutation within the first intron of PKP1 resulting in a premature stop codon, thereby explaining the inability to detect plakophilin-1 in the skin. Altogether, the clinical and pathological findings, along with the PKP1 mutation, were consistent with the diagnosis of ectodermal dysplasia-skin fragility syndrome with plakophilin-1 deficiency. This is the first occurrence of ectodermal dysplasia-skin fragility syndrome in an animal species. Controlled mating of carrier dogs would yield puppies that could, in theory, be tested for gene therapy of this rare but severe skin disease of children.
Highlights
Congenital and hereditary disorders of skin adhesion are collectively grouped under the umbrella of epidermolysis bullosa (EB), and these diseases are further separated depending upon the level of intracutaneous cleavage [1]
Chesapeake Bay retriever (CBR) puppies were diagnosed with ectodermal dysplasia-skin fragility syndrome (ED-SFS); six of the affected puppies died within hours or days of birth
We report a novel spontaneously-arising congenital and hereditary disease of dogs caused by a mutation in PKP1, which results in a very short protein, abnormal and dysfunctional superficial epidermal desmosomes, profound keratinocyte acantholysis and superficial epidermal sloughing occurring at birth
Summary
Congenital and hereditary disorders of skin adhesion are collectively grouped under the umbrella of epidermolysis bullosa (EB), and these diseases are further separated depending upon the level of intracutaneous cleavage [1]. A recent consensus classification distinguished four major types of human EB, which included EB simplex (EBS), junctional EB, dystrophic EB and the Kindler syndrome; these variants exhibit skin clefting respectively in the epidermis itself, the basement membrane’s lamina lucida, the sub-lamina densa or multiple areas [1]. Among the subtypes of EB simplex, the suprabasal variants include lethal acantholytic EB due to mutations of the gene encoding desmoplakin, the ectodermal dysplasia-skin fragility syndrome (ED-SFS) with plakophilin-1 (PKP1) deficiency and EBS superficialis of unknown genetic cause [1]. The desmosomes are small and keratin filaments appear to separate from the desmosomal inner plaques [12]. In these patients, the expression of PKP1 is reduced to absent and that of desmoplakin changes from a typical intercellular to a cytoplasmic pattern. Individuals with one normal allele appear phenotypically normal [7]
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