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(https:\/\/doi.org\/10.1084\/jem.20240827) identified variants in HMCN1 that co-segregate with and account for variations in disease severity in individuals with a diagnosis of epidermolysis bullosa simplex (EBS) resulting from pathogenic variants in KRT14. The authors show that hemicentin-1 binds keratin 14 at the protein level and that silencing HMCN1 expression disrupts the organization of K14-containing filaments in epidermal keratinocytes and their attachment to the extracellular matrix. These findings address the clinical heterogeneity observed in EBS, a rare genetic skin disorder, with general implications for all genodermatoses.<\/jats:p>","DOI":"10.1084\/jem.20242377","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T02:20:59Z","timestamp":1737685259000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["A \u201csecond hit\u201d impacts disease severity in a dominantly inherited genetic skin disorder"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0680-2373","authenticated-orcid":true,"given":"Pierre A.","family":"Coulombe","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00jmfr291","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Michigan Medical School 1 Department of Cell and Developmental Biology, , Ann Arbor, MI,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00jmfr291","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Michigan Medical School 2 Department of Dermatology, , Ann Arbor, MI,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00jmfr291","id-type":"ROR","asserted-by":"publisher"}],"name":"Rogel Cancer Center, University of Michigan 3 , Ann Arbor, MI,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2025,2,20]]},"reference":[{"key":"2025022015174158400_bib1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20240827","author":"Bergson","year":"2025","journal-title":"J. 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