phenylephrine-hydrochloride and Parakeratosis

Hereditary nasal parakeratosis (HNPK), described in the Labrador Retriever breed, is a monogenic autosomal recessive disorder that causes crusts and fissures on the nasal planum of otherwise healthy dogs. Our group previously showed that this genodermatosis may be caused by a missense variant located in the SUV39H2 gene encoding a histone 3 lysine 9 methyltransferase, a chromatin modifying enzyme with a potential role in keratinocyte differentiation. In the present study, we investigated a litter of Greyhounds in which six out of eight puppies were affected with parakeratotic lesions restricted to the nasal planum. Clinically and histologically, the lesions were comparable to HNPK in Labrador Retrievers. Whole genome sequencing of one affected Greyhound revealed a 4-bp deletion at the 5'-end of intron 4 of the SUV39H2 gene that was absent in 188 control dog and three wolf genomes. The variant was predicted to disrupt the 5'-splice site with subsequent loss of SUV39H2 function. The six affected puppies were homozygous for the variant, whereas the two non-affected littermates were heterozygous. Genotyping of a larger cohort of Greyhounds revealed that the variant is segregating in the breed and that this breed might benefit from genetic testing to avoid carrier × carrier matings.

Topics: Animals; Breeding; Dog Diseases; Dogs; Genotype; Histone-Lysine N-Methyltransferase; Nose; Parakeratosis; Phenotype; Sequence Deletion

Hereditary nasal parakeratosis (HNPK), an inherited monogenic autosomal recessive skin disorder, leads to crusts and fissures on the nasal planum of Labrador Retrievers. We performed a genome-wide association study (GWAS) using 13 HNPK cases and 23 controls. We obtained a single strong association signal on chromosome 2 (p(raw) = 4.4×10⁻¹⁴). The analysis of shared haplotypes among the 13 cases defined a critical interval of 1.6 Mb with 25 predicted genes. We re-sequenced the genome of one case at 38× coverage and detected 3 non-synonymous variants in the critical interval with respect to the reference genome assembly. We genotyped these variants in larger cohorts of dogs and only one was perfectly associated with the HNPK phenotype in a cohort of more than 500 dogs. This candidate causative variant is a missense variant in the SUV39H2 gene encoding a histone 3 lysine 9 (H3K9) methyltransferase, which mediates chromatin silencing. The variant c.972T>G is predicted to change an evolutionary conserved asparagine into a lysine in the catalytically active domain of the enzyme (p.N324K). We further studied the histopathological alterations in the epidermis in vivo. Our data suggest that the HNPK phenotype is not caused by hyperproliferation, but rather delayed terminal differentiation of keratinocytes. Thus, our data provide evidence that SUV39H2 is involved in the epigenetic regulation of keratinocyte differentiation ensuring proper stratification and tight sealing of the mammalian epidermis.

Topics: Animals; Base Sequence; Cell Differentiation; Dog Diseases; Dogs; Epigenesis, Genetic; Genetic Predisposition to Disease; Genome-Wide Association Study; Haplotypes; Histone-Lysine N-Methyltransferase; Humans; Keratinocytes; Methyltransferases; Mutation; Nose; Parakeratosis

Hereditary nasal dermatitis is reported in 14 Labrador Retrievers and 4 Labrador Retriever crosses. This appears to be a newly described inherited disorder for which an autosomal recessive mode of inheritance is suspected. The lesions were first noted between 6 and 12 months of age. Histopathological analysis revealed parakeratotic hyperkeratosis, often with marked multifocal accumulation of proteinaceous fluid between keratinocytes within the stratum corneum and superficial stratum spinosum. There was also a sub-basal lymphoplasmacytic infiltration within the superficial dermis. Immunohistochemistry staining for IgG (n = 4), distemper and papillomaviruses (n = 4) were negative, as were serum antinuclear antibody serology (n = 4) and fungal culture (n = 7). Electron microscopy revealed an altered cornification process: retention of nuclear chromatin, absence of lamellar bodies and marked intercellular oedema. Dogs did not respond to oral administration of zinc methionin (n = 3), cephalexin (n = 4), vitamin A alcohol (n = 1) or topical tretinoin (n = 1). Improvement of the lesions was obtained with topical vitamin E (n = 2), petroleum jelly (n = 2), and propylene glycol (n = 5).

Topics: Administration, Topical; Animals; Breeding; Dog Diseases; Dogs; Genetic Predisposition to Disease; Immunohistochemistry; Nose; Parakeratosis; Pedigree; Petrolatum; Propylene Glycol; Quebec; Vermont; Vitamin E

We report 11 new cases of hereditary nasal parakeratosis in Labrador retrievers. The disease was first observed when the dogs were 6 months to 2 years of age, and affected dogs of either sex and all coat colours. Hyperkeratosis and depigmentation were confined to the nasal planum, and affected dogs were otherwise healthy. The principal histological findings in biopsy specimens were marked diffuse parakeratotic hyperkeratosis, multiple intracorneal serum lakes and superficial interstitial-to-interface lymphoplasmacytic dermatitis. Topical applications of propylene glycol in water or white petrolatum were often effective for treatment of the dermatosis. However, continued applications were required to maintain a beneficial response. A retrospective histological study of parakeratotic inflammatory diseases of canine haired skin and inflammatory diseases of the canine nasal planum was performed. The degree of parakeratotic hyperkeratosis and the number and size of intracorneal serum lakes were evaluated. The degree of parakeratotic hyperkeratosis was greater in hereditary nasal parakeratosis specimens than that seen in discoid lupus erythematosus and Malassezia dermatitis. There were more serum lakes in hereditary nasal parakeratosis specimens than in specimens from dogs with discoid lupus erythematosus, Malassezia dermatitis, primary seborrheic dermatitis or zinc-responsive dermatosis. Significant differences in sizes of serum lakes (if present) were not seen.

Topics: Animals; Breeding; Dog Diseases; Dogs; Female; Genetic Predisposition to Disease; Immunohistochemistry; Male; New York; Nose; Parakeratosis; Petrolatum; Propylene Glycol; Retrospective Studies