{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:39:55Z","timestamp":1760402395623,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T00:00:00Z","timestamp":1588032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["CRSII3_160738 \/ 1"],"award-info":[{"award-number":["CRSII3_160738 \/ 1"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>A 4-month-old female Irish Terrier presented with a well demarcated ulcerative and crusting lesion in the right ear canal. Histological analysis revealed epidermal hyperplasia with severe acantholysis affecting all suprabasal layers of the epidermis, which prompted a presumptive diagnosis of canine Darier disease. The lesion was successfully treated by repeated laser ablation of the affected epidermis. Over the course of three years, the dog additionally developed three dermal nodules of up to 4 cm in diameter that were excised and healed without complications. Histology of the excised tissue revealed multiple infundibular cysts extending from the upper dermis to the subcutis. The cysts were lined by squamous epithelium, which presented with abundant acantholysis of suprabasal keratinocytes. Infundibular cysts represent a novel finding not previously reported in Darier patients. Whole genome sequencing of the affected dog was performed, and the functional candidate genes for Darier disease (ATP2A2) and Hailey-Hailey disease (ATP2C1) were investigated. The analysis revealed a heterozygous SINE insertion into the ATP2A2 gene, at the end of intron 14, close to the boundary of exon 15. Analysis of the ATP2A2 mRNA from skin of the affected dog demonstrated a splicing defect and marked allelic imbalance, suggesting nonsense-mediated decay of the resulting aberrant transcripts. As Darier disease in humans is caused by haploinsufficiency of ATP2A2, our genetic findings are in agreement with the clinical and histopathological data and support the diagnosis of canine Darier disease.<\/jats:p>","DOI":"10.3390\/genes11050481","type":"journal-article","created":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T01:29:15Z","timestamp":1588123755000},"page":"481","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["ATP2A2 SINE Insertion in an Irish Terrier with Darier Disease and Associated Infundibular Cyst Formation"],"prefix":"10.3390","volume":"11","author":[{"given":"Monika","family":"Linek","sequence":"first","affiliation":[{"name":"AniCura Tier\u00e4rztliche Spezialisten, 22043 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maren","family":"Doelle","sequence":"additional","affiliation":[{"name":"AniCura Tier\u00e4rztliche Spezialisten, 22043 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0553-4880","authenticated-orcid":false,"given":"Tosso","family":"Leeb","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"},{"name":"Dermfocus, University of Bern, 3001 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anina","family":"Bauer","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"},{"name":"Dermfocus, University of Bern, 3001 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabienne","family":"Leuthard","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"},{"name":"Dermfocus, University of Bern, 3001 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3798-5977","authenticated-orcid":false,"given":"Jan","family":"Henkel","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"},{"name":"Dermfocus, University of Bern, 3001 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7614-7207","authenticated-orcid":false,"given":"Danika","family":"Bannasch","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"},{"name":"Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8155-0041","authenticated-orcid":false,"given":"Vidhya","family":"Jagannathan","sequence":"additional","affiliation":[{"name":"Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"},{"name":"Dermfocus, University of Bern, 3001 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika M.","family":"Welle","sequence":"additional","affiliation":[{"name":"Dermfocus, University of Bern, 3001 Bern, Switzerland"},{"name":"Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/j.1749-6632.2009.04363.x","article-title":"Making an epidermis","volume":"1170","author":"Koster","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1038\/sj.jid.5701015","article-title":"Desmosomes: New perspectives on a classic","volume":"127","author":"Green","year":"2007","journal-title":"J. Investig. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/sj.jid.5701248","article-title":"Outside-in signaling through integrins and cadherins: A central mechanism to control epidermal growth and differentiation?","volume":"128","author":"Williamson","year":"2008","journal-title":"J. Investig. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1006\/excr.2002.5509","article-title":"Desmosome assembly in MDCK cells: Transport of precursors to the cell surface occurs by two phases of vesicular traffic and involves major changes in centrosome and Golgi location during a Ca2+ shift","volume":"276","author":"Burdett","year":"2002","journal-title":"Exp. Cell Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1046\/j.1523-1747.2002.19512.x","article-title":"Modulations in epidermal calcium regulate the expression of differentiation-specific markers","volume":"119","author":"Elias","year":"2002","journal-title":"J. Investig. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1002\/ajmg.c.30031","article-title":"Calcium pump disorders of the skin","volume":"131","author":"Foggia","year":"2004","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/6784","article-title":"Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease","volume":"21","author":"Sakuntabhai","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/humu.23164","article-title":"Mendelian disorders of cornification caused by defects in intracellular calcium pumps: Mutation update and database for variants in ATP2A2 and ATP2C1 associated with Darier disease and Hailey-Hailey disease","volume":"38","author":"Nellen","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/0190-9622(92)70154-8","article-title":"Darier-White disease: A review of the clinical features in 163 patients","volume":"27","author":"Burge","year":"1992","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/71701","article-title":"Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease","volume":"24","author":"Hu","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1172\/JCI21791","article-title":"Allelic loss underlies type 2 segmental Hailey-Hailey disease, providing molecular confirmation of a novel genetic concept","volume":"114","author":"Wiederholt","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/cup.13356","article-title":"Distinguishing histopathologic features of acantholytic dermatoses and the pattern of acantholytic hypergranulosis","volume":"46","author":"See","year":"2019","journal-title":"J. Cutan. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/j.1365-3164.2009.00821.x","article-title":"Dermatoses affecting desmosomes in animals: A mechanistic review of acantholytic blistering skin diseases","volume":"20","author":"Olivry","year":"2009","journal-title":"Vet. Dermatol."},{"key":"ref_14","first-page":"353","article-title":"Canine Benign Familial Chronic Pemphigus","volume":"Volume 2","author":"Ihrke","year":"1993","journal-title":"Advances in Veterinary Dermatology"},{"key":"ref_15","first-page":"190","article-title":"Dominantly inherited epidermal acantholysis in dogs, simulating human benign familial chronic pemphigus (Hailey Hailey disease)","volume":"136","author":"Sueki","year":"1997","journal-title":"Br. J. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1038\/sj.jid.5700091","article-title":"Consequences of depleted SERCA2-gated calcium stores in the skin","volume":"126","author":"Caldelari","year":"2006","journal-title":"J. Investig. Dermatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1111\/age.12834","article-title":"A comprehensive biomedical variant catalogue based on whole genome sequences of 582 dogs and eight wolves","volume":"50","author":"Jagannathan","year":"2019","journal-title":"Anim. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1093\/nar\/gku1174","article-title":"DoGSD: The dog and wolf genome SNP database","volume":"43","author":"Bai","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1038\/s41467-019-09373-w","article-title":"Whole genome sequencing of canids reveals genomic regions under selection and variants influencing morphology","volume":"10","author":"Plassais","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/nbt.1754","article-title":"Integrative genomics viewer","volume":"29","author":"Robinson","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1111\/j.1365-2133.1995.tb08682.x","article-title":"Comedonal Darier\u2019s disease","volume":"132","author":"Derrick","year":"1995","journal-title":"Br. J. Dermatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e307","DOI":"10.1016\/j.jaad.2013.08.035","article-title":"Comedonal Darier disease: Report of 2 cases","volume":"69","author":"Lora","year":"2013","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"97","DOI":"10.2165\/00128071-200304020-00003","article-title":"Darier\u2019s disease: Epidemiology, pathophysiology, and management","volume":"4","author":"Cooper","year":"2003","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1111\/ced.12078","article-title":"Treatment of Darier disease with oral alitretinoin","volume":"38","author":"Herzinger","year":"2013","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/0190-9622(90)70311-5","article-title":"Carbon dioxide laser vaporization of recalcitrant symptomatic plaques of Hailey-Hailey disease and Darier\u2019s disease","volume":"23","author":"McElroy","year":"1990","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1001\/archderm.135.4.423","article-title":"Efficacy of erbium:YAG laser ablation in Darier disease and Hailey-Hailey disease","volume":"135","author":"Beier","year":"1999","journal-title":"Arch. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"77","DOI":"10.3109\/14764172.2014.988728","article-title":"Significant alleviation of Darier\u2019s disease with fractional CO2 laser","volume":"17","author":"Benmously","year":"2015","journal-title":"J. Cosmet. Laser Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1093\/hmg\/8.9.1611","article-title":"Spectrum of novel ATP2A2 mutations in patients with Darier\u2019s disease","volume":"8","author":"Sakuntabhai","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e1548","DOI":"10.1002\/wrna.1548","article-title":"Nonsense-mediated mRNA decay: The challenge of telling right from wrong in a complex transcriptome","volume":"10","author":"Kishor","year":"2019","journal-title":"Wiley Interdiscip. Rev. RNA"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/5\/481\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:32:11Z","timestamp":1760362331000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/5\/481"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,28]]},"references-count":32,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["genes11050481"],"URL":"https:\/\/doi.org\/10.3390\/genes11050481","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2020,4,28]]}}}