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A Mutation in the SUV39H2 Gene in Labrador Retrievers with Hereditary Nasal Parakeratosis (HNPK) Provides Insights into the Epigenetics of Keratinocyte Differentiation
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نویسنده
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jagannathan v. ,bannoehr j. ,plattet p. ,hauswirth r. ,drögemüller c. ,drögemüller m. ,wiener d.j. ,doherr m. ,owczarek-lipska m. ,galichet a. ,welle m.m. ,tengvall k. ,bergvall k. ,lohi h. ,rüfenacht s. ,linek m. ,paradis m. ,müller e.j. ,roosje p. ,leeb t.
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منبع
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plos genetics - 2013 - دوره : 9 - شماره : 10
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چکیده
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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 (praw = 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. © 2013 jagannathan et al.
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آدرس
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institute of genetics,university of bern,bern,switzerland,dermfocus,university of bern,bern, Switzerland, dermfocus,university of bern,bern,switzerland,division of clinical dermatology,university of bern,bern, Switzerland, division of neuroscience,university of bern,bern, Switzerland, institute of genetics,university of bern,bern,switzerland,dermfocus,university of bern,bern, Switzerland, institute of genetics,university of bern,bern,switzerland,dermfocus,university of bern,bern, Switzerland, institute of genetics,university of bern,bern,switzerland,dermfocus,university of bern,bern, Switzerland, dermfocus,university of bern,bern,switzerland,institute of animal pathology,university of bern,bern, Switzerland, veterinary public health institute,university of bern,bern, Switzerland, institute of genetics,university of bern,bern,switzerland,dermfocus,university of bern,bern, Switzerland, dermfocus,university of bern,bern,switzerland,institute of animal pathology,university of bern,bern, Switzerland, dermfocus,university of bern,bern,switzerland,institute of animal pathology,university of bern,bern, Switzerland, science for life laboratory,department of medical biochemistry and microbiology,uppsala university,uppsala, Sweden, department of clinical sciences,swedish university of agricultural sciences,uppsala, Sweden, research programs unit,molecular neurology,university of helsinki,helsinki,finland,department of veterinary biosciences and department of medical genetics,university of helsinki,helsinki,finland,folkhälsan institute of genetics,helsinki, Finland, dermavet,tierklinik aarau-west,oberentfelden, Switzerland, tierärztliche spezialisten,hamburg, Germany, department of clinical sciences,university of montreal,st-hyacinthe,qc, Canada, dermfocus,university of bern,bern,switzerland,institute of animal pathology,university of bern,bern, Switzerland, dermfocus,university of bern,bern,switzerland,division of clinical dermatology,university of bern,bern, Switzerland, institute of genetics,university of bern,bern,switzerland,dermfocus,university of bern,bern, Switzerland
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Authors
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