{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T20:22:08Z","timestamp":1787170928554,"version":"build-2736575974"},"reference-count":21,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T00:00:00Z","timestamp":1710892800000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Dermatology"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Desmoplakin (DSP) is a desmosomal component expressed in skin and heart, essential for desmosome stability and intermediate filament connection. Pathogenic variants in the\n                    <jats:italic>DSP<\/jats:italic>\n                    gene encoding DSP, lead to heterogeneous skin, adnexa and heart\u2010related phenotypes, including skin fragility, woolly hair (WH), palmoplantar keratoderma (PPK) and arrhythmogenic\/dilated cardiomyopathy (ACM\/DCM). The ambiguity of computer\u2010based prediction analysis of pathogenicity and effect of\n                    <jats:italic>DSP<\/jats:italic>\n                    variants, indicates a necessity for functional analysis. Here, we report a heterozygous\n                    <jats:italic>DSP<\/jats:italic>\n                    variant that was not previously described, NM_004415.4:c.3337C&gt;T (NM_004415.4(NP_004406.2):p.(Arg1113*)) in a patient with PPK, WH and ACM. RNA and protein analysis revealed ~50% reduction of\n                    <jats:italic>DSP<\/jats:italic>\n                    mRNA and protein expression. Patient's keratinocytes showed fragile cell\u2013cell connections and perinuclear retracted intermediate filaments. Epidermal growth factor receptor (EGFR) is a transmembrane protein expressed in the basal epidermal layer involved in proliferation and differentiation, processes that are disrupted in the development of PPK, and in the regulation of the desmosome. In skin of the abovementioned patient, evident EGFR upregulation was observed. EGFR inhibition in patient's keratinocytes strongly increased DSP expression at the plasma membrane, improved intermediate filament connection with the membrane edges and reduced the cell\u2013cell fragility. This cell phenotypic recovery was due to a translocation of DSP to the plasma membrane together with an increased number of desmosomes. These results indicate a therapeutic potential of EGFR inhibitors for disorders caused by\n                    <jats:italic>DSP<\/jats:italic>\n                    haploinsufficiency.\n                  <\/jats:p>","DOI":"10.1111\/exd.15046","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T02:39:54Z","timestamp":1710988794000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Epidermal growth factor receptor inhibition leads to cellular phenotype correction of\n                    <i>DSP<\/i>\n                    \u2010mutated keratinocytes"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4211-2783","authenticated-orcid":false,"given":"Daniela","family":"Andrei","sequence":"first","affiliation":[{"name":"Department of Dermatology Expertise Center for Blistering Diseases, University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7550-6386","authenticated-orcid":false,"given":"Jeroen","family":"Bremer","sequence":"additional","affiliation":[{"name":"Department of Dermatology Expertise Center for Blistering Diseases, University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duco","family":"Kramer","sequence":"additional","affiliation":[{"name":"Department of Dermatology Expertise Center for Blistering Diseases, University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albertine M.","family":"Nijenhuis","sequence":"additional","affiliation":[{"name":"Department of Dermatology Expertise Center for Blistering Diseases, University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marije","family":"van der Molen","sequence":"additional","affiliation":[{"name":"Department of Dermatology Expertise Center for Blistering Diseases, University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles F. H.","family":"Diercks","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C.","family":"van den Akker","sequence":"additional","affiliation":[{"name":"Department of Genetics Expertise Center for Blistering Diseases, University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8513-2296","authenticated-orcid":false,"given":"Mathilde C. S. C.","family":"Vermeer","sequence":"additional","affiliation":[{"name":"Department of Cardiology University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"van der Meer","sequence":"additional","affiliation":[{"name":"Department of Cardiology University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C.","family":"Bolling","sequence":"additional","affiliation":[{"name":"Department of Dermatology Expertise Center for Blistering Diseases, University of Groningen, University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,3,20]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms231810765"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.2004.05996.x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2230.2005.01736.x"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568026620666200303123102"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200809044"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.22599"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e08-04-0356"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M405123200"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81894-2"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12616168"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/exd.14571"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00418-020-01846-0"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1942"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.1.143"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamadermatol.2019.4141"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1747.1999.00783.x"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdm222"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2020.07.006"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.163763"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.2022.36.S1.R2705"}],"container-title":["Experimental Dermatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/exd.15046","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,21]],"date-time":"2024-12-21T04:02:10Z","timestamp":1734753730000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/exd.15046"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3]]},"references-count":21,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2024,3]]}},"alternative-id":["10.1111\/exd.15046"],"URL":"https:\/\/doi.org\/10.1111\/exd.15046","archive":["Portico"],"relation":{},"ISSN":["0906-6705","1600-0625"],"issn-type":[{"value":"0906-6705","type":"print"},{"value":"1600-0625","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3]]},"assertion":[{"value":"2023-10-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e15046"}}