Jagannathan, Vidhya

Kiener, Sarah

Leeb, Tosso

Soto, Sara

Åhman, Susanne

English

BORIS Portal  Bern Open Repository and Information System

Animal Genetics. 2023;00:1–3.    | 1wileyonlinelibrary.com/journal/ageB R I E F  R E P O R THeterozygous KRT10 missense variant in a Chihuahua with severe epidermolytic ichthyosisBACKGROU N DIchthyoses are a group of heritable cornification dis-orders. Various different subtypes are known and they can be classified based on the genetic background and underlying molecular mechanisms (Gutiérrez- Cerrajero et al., 2023). A rare form of ichthyosis is termed epider-molytic hyperkeratosis, which is mainly caused by vari-ants in KRT1 and KRT10 (Fuchs & Green, 1980; Peter Rout et al., 2019). The encoded proteins, keratin 1 and keratin 10, assemble into intermediate filaments that form the cytoskeleton in differentiated keratinocytes, providing mechanical resilience (Fuchs & Green, 1980; Gutiérrez- Cerrajero et al., 2023; Syder et al., 1994).Epidermolytic hyperkeratosis in humans pre-dominantly follows an autosomal dominant mode of inheritance, with half of the cases resulting from de novo mutation events (Chipev et al.,  1994; Peter Rout et al.,  2019). In dogs, one occurrence of KRT10- associated recessive epidermolytic hyperkeratosis has been described in Norfolk Terriers owing to a homozy-gous splice- site variant (Credille et al., 2005).A NA LYSESAn 11- month- old male Chihuahua was presented with severe skin lesions gradually progressing from 5 months of age. Clinical examination revealed severe, multifocal hyperkeratosis, mainly affecting paw pads, axillas and the skin around the anus, lips and eyes (Figure 1). Three skin punch biopsies from axilla, lip and paw pad were taken under general anesthesia for diagnostic purposes. All samples displayed similar changes, characterized by marked epidermal hyperplasia and orthokeratotic hyperkeratosis with hypergranulosis, forming papillary Received: 12 June 2023 | Accepted: 12 June 2023DOI: 10.1111/age.13341  This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.© 2023 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.F I G U R E  1  Clinical phenotype of the affected Chihuahua. (a) Severe, focal and macroscopically laminar hyperkeratosis in the axillae with concurrent severe hair loss and moderate seborrhoeic changes. (b) Close up of right axilla. (c) Rim of hyperkeratosis around lip commisure and rima. (d– f) Severe paw pad hyperkeratosis and mild palmar and plantar erythema affecting all pads on all four paws.2 |   KIENER et al.projections on the skin surface These histopathologi-cal findings, together with the anamnesis and clini-cal findings, were characteristic for an epidermolytic hyperkeratosis.Whole genome sequencing at 28× coverage was per-formed on genomic DNA extracted from leukocytes. Data processing was done as previously described (Jagannathan et al.,  2019), using the genome reference assembly UU_Cfam_GSD_1.0. We identified 72 het-erozygous and five homozygous private protein chang-ing variants in the case by comparing its sequence data with 926 genetically diverse control genomes (Tables  S1 and S2). One of these variants was located in KRT10, a known ichthyosis candidate gene. The heterozygous missense variant, Chr9:21814695G>A, XM_038547368.1:c.437G>A, was predicted to change an evolutionarily conserved arginine in the coil 1A domain, XP_038403296.1:p.(Arg146His). The presence of the het-erozygous genotype at the position of the variant was confirmed by Sanger sequencing. The genotypes of 40 additional Chihuahuas from the Vetsuisse Biobank were homozygous wild type. We speculate that this variant has most likely arisen de novo in the affected dog; how-ever, samples from the parents to confirm this hypothe-sis were not available.CONCLUSIONSThe identified KRT10 missense variant is most likely causative for the observed epidermolytic hyperkeratosis in the Chihuahua. The variant affects a conserved CpG dinucleotide within an arginine codon. Heterozygous variants affecting human Arg156, homologous to ca-nine Arg146, have been described in several human pa-tients with epidermolytic hyperkeratosis, suggesting this residue to be a mutational hot spot (Cheng et al., 1992; Chipev et al.,  1994; Rothnagel et al.,  1992, 1993; Syder et al., 1994).ACK NO W LE DGE M EN TSThe authors would like to thank the dog owner for do-nating samples and information. The authors also wish to thank the Next Generation Sequencing Platform of the University of Bern for performing whole- genome sequencing experiments and the Interfaculty Bioinformatics Unit for providing high performance computing infrastructure. We acknowledge the DBVDC consortium, the Dog10K genomes project and all re-searchers who deposited dog or wolf whole genome sequencing data into public databases. Open access funding provided by Universitat Bern.F U N DI NG I N FOR M AT IONThis study was funded by the Swiss National Science Foundation, grant number 310030_200354.CON F LICT OF I N T ER E ST STAT EM EN TThe authors declare no conflicts of interest.DATA AVA I LA BI LI T Y STAT EM EN TAll underlying raw data are freely available. Accession numbers of the whole genome sequences used in this study are listed in Table S1.ET H IC S STAT EM EN TThe examinations of the affected dog were done with the consent of the owner in the framework of veterinary care and diagnostics and did not constitute an animal experi-ment. The collection of blood samples from control dogs was approved by the Cantonal Committee for Animal Experiments (Canton of Bern; permit BE94/2022).Sarah Kiener1,2Susanne Åhman3Vidhya Jagannathan1Sara Soto2,4Tosso Leeb1,21Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland2DermFocus, University of Bern, Bern, Switzerland3VetaDerm Veterinärklinik, Lomma, Sweden4Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, SwitzerlandCorrespondenceTosso Leeb, Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.Email: tosso.leeb@unibe.chORCI DTosso Leeb   https://orcid.org/0000-0003-0553-4880 R E F ER E NC E SCheng, J., Syder, A.J., Yu, Q.- C., Letal, A., Paller, A.S. & Fuchs, E. (1992) The genetic basis of epidermolytic hyperkeratosis: a disorder of differentiation- specific epidermal keratin genes. Cell, 70(5), 811– 819. Available from: https://doi.org/10.1016/0092-8674(92)90314-3Chipev, C.C., Yang, J.M., DiGiovanna, J.J., Steinert, P.M., Marekov, L., Compton, J.G. et al. (1994) Preferential sites in keratin 10 that are mutated in epidermolytic hyperkeratosis. American Journal of Human Genetics, 54(2), 179– 190.Credille, K.M., Barnhart, K.F., Minor, J.S. & Dunstan, R.W. (2005) Mild recessive epidermolytic hyperkeratosis associated with a novel keratin 10 donor splice- site mutation in a family of Norfolk terrier dogs. British Journal of Dermatology, 153(1), 51– 58. Available from: https://doi.org/10.1111/j.1365-2133.2005.06735.xFuchs, E. & Green, H. (1980) Changes in keratin gene expression during terminal differentiation of the keratinocyte. Cell, 19(4), 1033– 1042. Available from: https://doi.org/10.1016/0092-8674(80)90094-XGutiérrez- Cerrajero, C., Sprecher, E., Paller, A.S., Akiyama, M., Mazereeuw- Hautier, J., Hernández- Martín, A. et al. (2023) Ichthyosis. Nature Reviews Disease Primers, 9(1), 2. Available from: https://doi.org/10.1038/s41572-022-00412-3 13652052, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/age.13341 by Universitaet Bern, Wiley Online Library on [20/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License   | 3KRT10 VARIANT IN A DOG WITH ICHTHYOSISJagannathan, V., Drögemüller, C., Leeb, T., Aguirre, G., André, C., Bannasch, D. et al. (2019) A comprehensive biomedical variant catalogue based on whole genome sequences of 582 dogs and eight wolves. Animal Genetics, 50(6), 695– 704. Available from: https://doi.org/10.1111/age.12834Peter Rout, D., Nair, A., Gupta, A. & Kumar, P. (2019) Epidermolytic hyperkeratosis: clinical update. Clinical, Cosmetic and Investigational Dermatology, 12, 333– 344. Available from: https://doi.org/10.2147/CCID.S166849Rothnagel, J.A., Dominey, A.M., Dempsey, L.D., Longley, M.A., Greenhalgh, D.A., Gagne, T.A. et al. (1992) Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkera-tosis. Science, 257(5073), 1128– 1130. Available from: https://doi.org/10.1126/scien ce.257.5073.1128Rothnagel, J.A., Fisher, M.P., Axtell, S.M., Pittelkow, M.R., Anton- Lamprecht, I., Huber, M. et al. (1993) A mutational hot spot in keratin 10 (KRT 10) in patients with epidermolytic hyperkerato-sis. Human Molecular Genetics, 2(12), 2147– 2150. Available from: https://doi.org/10.1093/hmg/2.12.2147Syder, A.J., Yu, Q.C., Paller, A.S., Giudice, G., Pearson, R. & Fuchs, E. (1994) Genetic mutations in the K1 and K10 genes of patients with epidermolytic hyperkeratosis. Correlation between loca-tion and disease severity. Journal of Clinical Investigation, 93(4), 1533– 1542. Available from: https://doi.org/10.1172/JCI11 7132SU PPORT I NG I N FOR M AT IONAdditional supporting information can be found online in the Supporting Information section at the end of this article. 13652052, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/age.13341 by Universitaet Bern, Wiley Online Library on [20/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Heterozygous KRT10 missense variant in a Chihuahua with severe epidermolytic ichthyosis.

Sarah Kiener

Susanne Åhman

Vidhya Jagannathan

Sara Soto

Tosso Leeb

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 missense variant in a Chihuahua with severe epidermolytic ichthyosis 

https://boris.unibe.ch/183535/1/Animal_Genetics_-_2023_-_Kiener_-_Heterozygous_KRT10_missense_variant_in_a_Chihuahua_with_severe_epidermolytic_ichthyosis.pdf

Heterozygous KRT10 missense variant in a Chihuahua with severe epidermolytic ichthyosis.

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