A mutation in the SUV39H2 gene in Labrador Retrievers with hereditary nasal parakeratosis (HNPK) provides insights into the epigenetics of keratinocyte differentiation

• Published in: PLoS genetics 2013-10, Vol.9 (10), p.e1003848-e1003848
• Main Authors: Jagannathan, Vidhya, Bannoehr, Jeanette, Plattet, Philippe, Hauswirth, Regula, Drögemüller, Cord, Drögemüller, Michaela, Wiener, Dominique J, Doherr, Marcus, Owczarek-Lipska, Marta, Galichet, Arnaud, Welle, Monika M, Tengvall, Katarina, Bergvall, Kerstin, Lohi, Hannes, Rüfenacht, Silvia, Linek, Monika, Paradis, Manon, Müller, Eliane J, Roosje, Petra, Leeb, Tosso
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Cell Differentiation; Dog Diseases - etiology; Dog Diseases - genetics; Dogs; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Gene mutations; Genetic aspects; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Haplotypes; Histone-Lysine N-Methyltransferase - genetics; Humans; Keratinocytes; Keratinocytes - metabolism; Keratinocytes - pathology; Keratosis; Labrador dogs; Methyltransferases - genetics; Mutation; Nose; Parakeratosis - genetics; Parakeratosis - pathology; Pathobiology; Patobiologi; Physiological aspects
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1003848

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.