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

Jagannathan, Vidhya; Bannoehr, Jeanette; Plattet, Philippe; Hauswirth, Regula; Drögemüller, Cord; Drögemüller, Michaela; Wiener, Dominique Judith; Doherr, Marcus; Owczarek-Lipska, Marta; Galichet, Arnaud; Welle, Monika Maria; Tengvall, Katarina; Bergvall, Kerstin; Lohi, Hannes; Rüfenacht, Silvia; Linek, Monika; Paradis, Manon; Müller, Eliane Jasmine; Roosje, Petra and Leeb, Tosso (2013). A mutation in the SUV39H2 gene in Labrador Retrievers with hereditary nasal parakeratosis (HNPK) provides insights into the epigenetics of keratinocyte differentiation. PLoS genetics, 9(10), e1003848. Public Library of Science 10.1371/journal.pgen.1003848

[img]
Preview
Text
journal.pgen.1003848.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (1MB) | Preview

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > DermFocus
05 Veterinary Medicine > Research Foci > Veterinary Public Health / Herd Health Management
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV)
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Veterinary Public Health Institute
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Experimental Clinical Research
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)
05 Veterinary Medicine > Department of Clinical Veterinary Medicine (DKV) > DKV - Dermatology
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

UniBE Contributor:

Jagannathan, Vidya; Bannoehr, Jeanette; Plattet, Philippe; Hauswirth, Regula; Drögemüller, Cord; Drögemüller, Michaela; Wiener, Dominique Judith; Doherr, Marcus; Galichet, Arnaud; Welle, Monika Maria; Müller, Eliane Jasmine; Roosje, Petra and Leeb, Tosso

Subjects:

500 Science > 590 Animals (Zoology)
600 Technology > 630 Agriculture

ISSN:

1553-7390

Publisher:

Public Library of Science

Language:

English

Submitter:

Susanne Portner

Date Deposited:

24 Jul 2014 15:29

Last Modified:

11 Oct 2018 17:03

Publisher DOI:

10.1371/journal.pgen.1003848

PubMed ID:

24098150

BORIS DOI:

10.7892/boris.43860

URI:

https://boris.unibe.ch/id/eprint/43860

Actions (login required)

Edit item Edit item
Provide Feedback