A mutation in the SUV39H2 gene in Labrador Retrievers with hereditary nasal parakeratosis (HNPK) provides insights into the epigenetics of keratinocyte differentiation.
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 s...
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doaj-3d8a63b89ffb4466b2f4cfe3cd64012b2020-11-24T22:20:16ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-01-01910e100384810.1371/journal.pgen.1003848A mutation in the SUV39H2 gene in Labrador Retrievers with hereditary nasal parakeratosis (HNPK) provides insights into the epigenetics of keratinocyte differentiation.Vidhya JagannathanJeanette BannoehrPhilippe PlattetRegula HauswirthCord DrögemüllerMichaela DrögemüllerDominique J WienerMarcus DoherrMarta Owczarek-LipskaArnaud GalichetMonika M WelleKatarina TengvallKerstin BergvallHannes LohiSilvia RüfenachtMonika LinekManon ParadisEliane J MüllerPetra RoosjeTosso LeebHereditary 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.http://europepmc.org/articles/PMC3789836?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Vidhya Jagannathan Jeanette Bannoehr Philippe Plattet Regula Hauswirth Cord Drögemüller Michaela Drögemüller Dominique J Wiener Marcus Doherr Marta Owczarek-Lipska Arnaud Galichet Monika M Welle Katarina Tengvall Kerstin Bergvall Hannes Lohi Silvia Rüfenacht Monika Linek Manon Paradis Eliane J Müller Petra Roosje Tosso Leeb |
spellingShingle |
Vidhya Jagannathan Jeanette Bannoehr Philippe Plattet Regula Hauswirth Cord Drögemüller Michaela Drögemüller Dominique J Wiener Marcus Doherr Marta Owczarek-Lipska Arnaud Galichet Monika M Welle Katarina Tengvall Kerstin Bergvall Hannes Lohi Silvia Rüfenacht Monika Linek Manon Paradis Eliane J Müller Petra Roosje Tosso Leeb A mutation in the SUV39H2 gene in Labrador Retrievers with hereditary nasal parakeratosis (HNPK) provides insights into the epigenetics of keratinocyte differentiation. PLoS Genetics |
author_facet |
Vidhya Jagannathan Jeanette Bannoehr Philippe Plattet Regula Hauswirth Cord Drögemüller Michaela Drögemüller Dominique J Wiener Marcus Doherr Marta Owczarek-Lipska Arnaud Galichet Monika M Welle Katarina Tengvall Kerstin Bergvall Hannes Lohi Silvia Rüfenacht Monika Linek Manon Paradis Eliane J Müller Petra Roosje Tosso Leeb |
author_sort |
Vidhya Jagannathan |
title |
A mutation in the SUV39H2 gene in Labrador Retrievers with hereditary nasal parakeratosis (HNPK) provides insights into the epigenetics of keratinocyte differentiation. |
title_short |
A mutation in the SUV39H2 gene in Labrador Retrievers with hereditary nasal parakeratosis (HNPK) provides insights into the epigenetics of keratinocyte differentiation. |
title_full |
A mutation in the SUV39H2 gene in Labrador Retrievers with hereditary nasal parakeratosis (HNPK) provides insights into the epigenetics of keratinocyte differentiation. |
title_fullStr |
A mutation in the SUV39H2 gene in Labrador Retrievers with hereditary nasal parakeratosis (HNPK) provides insights into the epigenetics of keratinocyte differentiation. |
title_full_unstemmed |
A mutation in the SUV39H2 gene in Labrador Retrievers with hereditary nasal parakeratosis (HNPK) provides insights into the epigenetics of keratinocyte differentiation. |
title_sort |
mutation in the suv39h2 gene in labrador retrievers with hereditary nasal parakeratosis (hnpk) provides insights into the epigenetics of keratinocyte differentiation. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2013-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC3789836?pdf=render |
work_keys_str_mv |
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