{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T19:44:03Z","timestamp":1792698243275,"version":"4.5.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T00:00:00Z","timestamp":1739923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373500"],"award-info":[{"award-number":["82373500"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373459"],"award-info":[{"award-number":["82373459"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Congenital ichthyoses comprise a group of skin scaling diseases with clinical and genetic heterogeneity. They can be subclassified into syndromic and nonsyndromic forms. Syndromic ichthyoses affect organs beyond the skin. An increasing number of causative genes have been identified.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To identify the causative gene and the underlying pathogenesis of a previously unreported syndromic ichthyosis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Whole-exome sequencing (WES), combined with Sanger sequencing, was used to identify the genetic defect. Protein structural modelling and dual-luciferase reporter assays were used to investigate the effects of the pathogenic variants on Kr\u00fcppel-like factor 4 (KLF4). A human embryonic stem cell (hESC) H9 line harbouring the pathogenic variant was developed into a skin organoid for morphological observation and RNA sequencing analysis. The expression of candidate target genes was further validated in patient skin samples using quantitative reverse transcriptase polymerase chain reaction and immunofluorescence.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We enrolled four unrelated patients with a syndromic ichthyosis that predominantly manifested as ichthyosis, palmoplantar keratoderma, hypotrichosis, periorificial keratosis, nail dystrophy and extracutaneous involvement. WES identified two heterozygous missense variants, c.1322A&amp;gt;G (p.Asp441Gly) and c.1323T&amp;gt;A (p.Asp441Glu), in KLF4 in all four patients. Protein modelling predicted that the substitutions of the affected residue, Asp441, were likely to affect the stability of the local \u03b1-helix structure. Both variants exhibited reduced transcriptional activity. Skin organoids derived from hESC-H9 cells harbouring the heterozygous c.1323T&amp;gt;A variant displayed defects in epithelial morphogenesis and abnormal expression of keratinocyte differentiation-related genes and Wnt signalling genes. Decreased expression of KLK7 and WNT10A, which are vital for skin desquamation and multiorgan development, respectively, was detected in patient skin lesions.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Loss-of-function variants affecting residue Asp441 of KLF4 cause an autosomal dominant syndromic ichthyosis with multiorgan involvement. These variants impair KLF4 transcriptional activity, leading to the downregulation of multiple genes, particularly KLK7 and WNT10A. This may disrupt the skin desquamation process and affect multiorgan development in the patients.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bjd\/ljaf062","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T15:56:26Z","timestamp":1739980586000},"page":"136-146","source":"Crossref","is-referenced-by-count":8,"title":["Variants in <i>KLF4<\/i> affecting residue Asp441 cause an autosomal dominant syndromic ichthyosis"],"prefix":"10.1093","volume":"193","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7683-5392","authenticated-orcid":false,"given":"Zijuan","family":"Wang","sequence":"first","affiliation":[{"name":"Dermatology Hospital, Southern Medical University , Guangzhou ,","place":["China"]},{"name":"Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"Dermatology Hospital, Southern Medical University , Guangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oded","family":"Wechsberg","sequence":"additional","affiliation":[{"name":"Pediatric Genetics Unit, Schneider Children's Medical Center of Israel , Petah Tikva ,","place":["Israel"]},{"name":"Maccabi Healthcare Services , Tel Aviv ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Liang","sequence":"additional","affiliation":[{"name":"Dermatology Hospital, Southern Medical University , Guangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7780-6542","authenticated-orcid":false,"given":"Catherine E","family":"Keegan","sequence":"additional","affiliation":[{"name":"Division of Pediatric Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics, University of Michigan Medical School , Ann Arbor, MI ,","place":["USA"]},{"name":"Department of Human Genetics, University of Michigan Medical School , Ann Arbor, MI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Sloan-Heggen","sequence":"additional","affiliation":[{"name":"Division of Pediatric Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics, University of Michigan Medical School , Ann Arbor, MI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Guangzhou First People\u2019s Hospital , Guangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyang","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Central South University Xiangya Medical College Affiliated Children\u2019s Hospital, Hunan Children\u2019s Hospital , Changsha ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5414-1472","authenticated-orcid":false,"given":"Huijun","family":"Wang","sequence":"additional","affiliation":[{"name":"Dermatology Hospital, Southern Medical University , Guangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9323-2035","authenticated-orcid":false,"given":"Zhimiao","family":"Lin","sequence":"additional","affiliation":[{"name":"Dermatology Hospital, Southern Medical University , Guangzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,2,19]]},"reference":[{"key":"2025062423151823800_ljaf062-B1","first-page":"23","article-title":"Syndromic ichthyoses","volume":"35","author":"Fischer","year":"2023","journal-title":"Med Genet"},{"key":"2025062423151823800_ljaf062-B2","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.cell.2006.07.024","article-title":"Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors","volume":"126","author":"Takahashi","year":"2006","journal-title":"Cell"},{"key":"2025062423151823800_ljaf062-B3","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1093\/nar\/28.5.1106","article-title":"Transactivation and growth suppression by the gut-enriched Kruppel-like factor (Kruppel-like factor 4) are dependent on acidic amino acid residues and protein-protein interaction","volume":"28","author":"Geiman","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"2025062423151823800_ljaf062-B4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.gene.2017.02.025","article-title":"Kr\u00fcppel-like factor 4 (KLF4): What we currently know","volume":"611","author":"Ghaleb","year":"2017","journal-title":"Gene"},{"key":"2025062423151823800_ljaf062-B5","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/11926","article-title":"Klf4 is a transcription factor required for establishing the barrier function of the skin","volume":"22","author":"Segre","year":"1999","journal-title":"Nat Genet"},{"key":"2025062423151823800_ljaf062-B6","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/j.gim.2022.01.009","article-title":"Loss-of-function variants in KLF4 underlie autosomal dominant palmoplantar keratoderma","volume":"24","author":"Malovitski","year":"2022","journal-title":"Genet Med"},{"key":"2025062423151823800_ljaf062-B7","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1093\/bjd\/ljae275","article-title":"A loss-of-function variant in KLF4 affecting zinc finger motifs causes progressive symmetric erythrokeratodermia","volume":"191","author":"Wang","year":"2024","journal-title":"Br J Dermatol"},{"key":"2025062423151823800_ljaf062-B8","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1161\/CIRCRESAHA.121.318307","article-title":"Advances in lymphedema","volume":"128","author":"Rockson","year":"2021","journal-title":"Circ Res"},{"key":"2025062423151823800_ljaf062-B9","doi-asserted-by":"crossref","first-page":"894","DOI":"10.3390\/medicina59050894","article-title":"Current concepts in the management of primary lymphedema","volume":"59","author":"Senger","year":"2023","journal-title":"Medicina"},{"key":"2025062423151823800_ljaf062-B10","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/s41572-021-00309-7","article-title":"Primary lymphoedema","volume":"7","author":"Brouillard","year":"2021","journal-title":"Nat Rev Dis Primers"},{"key":"2025062423151823800_ljaf062-B11","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1002\/humu.22844","article-title":"GeneMatcher: a matching tool for connecting investigators with an interest in the same gene","volume":"36","author":"Sobreira","year":"2015","journal-title":"Hum Mutat"},{"key":"2025062423151823800_ljaf062-B12","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.3324\/haematol.2018.192773","article-title":"RUNX1 inhibits proliferation and induces apoptosis of t(8;21) leukemia cells via KLF4-mediated transactivation of P57","volume":"104","author":"Liu","year":"2019","journal-title":"Haematologica"},{"key":"2025062423151823800_ljaf062-B13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/10408363.2020.1775171","article-title":"The role of kallikreins in inflammatory skin disorders and their potential as therapeutic targets","volume":"58","author":"Di Paolo","year":"2021","journal-title":"Crit Rev Clin Lab Sci"},{"key":"2025062423151823800_ljaf062-B14","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1111\/j.0022-202X.2004.22512.x","article-title":"Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE\/KLK5\/hK5 and SCCE\/KLK7\/hK7","volume":"122","author":"Caubet","year":"2004","journal-title":"J Invest Dermatol"},{"key":"2025062423151823800_ljaf062-B15","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1101\/gad.246579.114","article-title":"ZNF750 interacts with KLF4 and RCOR1, KDM1A, and CTBP1\/2 chromatin regulators to repress epidermal progenitor genes and induce differentiation genes","volume":"28","author":"Boxer","year":"2014","journal-title":"Genes Dev"},{"key":"2025062423151823800_ljaf062-B16","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.cell.2017.05.016","article-title":"Wnt\/beta-catenin signaling, disease, and emerging therapeutic modalities","volume":"169","author":"Nusse","year":"2017","journal-title":"Cell"},{"key":"2025062423151823800_ljaf062-B17","doi-asserted-by":"crossref","first-page":"15397","DOI":"10.1038\/ncomms15397","article-title":"WNT10A mutation causes ectodermal dysplasia by impairing progenitor cell proliferation and KLF4-mediated differentiation","volume":"8","author":"Xu","year":"2017","journal-title":"Nat Commun"},{"key":"2025062423151823800_ljaf062-B18","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1111\/bjd.20601","article-title":"WNT10A, dermatology and dentistry","volume":"185","author":"Doolan","year":"2021","journal-title":"Br J Dermatol"},{"key":"2025062423151823800_ljaf062-B19","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.devcel.2015.05.025","article-title":"Regeneration of sensory hair cells requires localized interactions between the Notch and Wnt pathways","volume":"34","author":"Romero-Carvajal","year":"2015","journal-title":"Dev Cell"},{"key":"2025062423151823800_ljaf062-B20","doi-asserted-by":"crossref","first-page":"e0181549","DOI":"10.1371\/journal.pone.0181549","article-title":"Myeloid Wnt ligands are required for normal development of dermal lymphatic vasculature","volume":"12","author":"Muley","year":"2017","journal-title":"PLOS ONE"},{"key":"2025062423151823800_ljaf062-B21","doi-asserted-by":"crossref","first-page":"34355","DOI":"10.1074\/jbc.R100043200","article-title":"Kruppel-like factors: three fingers in many pies","volume":"276","author":"Bieker","year":"2001","journal-title":"J Biol Chem"},{"key":"2025062423151823800_ljaf062-B22","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/s41420-023-01416-y","article-title":"KLF4 transcription factor in tumorigenesis","volume":"9","author":"He","year":"2023","journal-title":"Cell Death Discov"},{"key":"2025062423151823800_ljaf062-B23","doi-asserted-by":"crossref","first-page":"3137","DOI":"10.1182\/blood-2011-04-349985","article-title":"Mutations in the second zinc finger of human EKLF reduce promoter affinity but give rise to benign and disease phenotypes","volume":"118","author":"Singleton","year":"2011","journal-title":"Blood"},{"key":"2025062423151823800_ljaf062-B24","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.ajhg.2010.10.010","article-title":"A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia","volume":"87","author":"Arnaud","year":"2010","journal-title":"Am J Hum Genet"},{"key":"2025062423151823800_ljaf062-B25","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/978-3-031-62731-6_10","article-title":"Erythroid Kr\u00fcppel-like factor (KLF1): a surprisingly versatile regulator of erythroid differentiation","volume":"1459","author":"Bieker","year":"2024","journal-title":"Adv Exp Med Biol"},{"key":"2025062423151823800_ljaf062-B26","doi-asserted-by":"crossref","first-page":"15151","DOI":"10.1073\/pnas.1004996107","article-title":"Severe anemia in the Nan mutant mouse caused by sequence-selective disruption of erythroid Kr\u00fcppel-like factor","volume":"107","author":"Siatecka","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2025062423151823800_ljaf062-B27","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1046\/j.1365-2133.1998.02452.x","article-title":"The expression of stratum corneum chymotryptic enzyme in human anagen hair follicles: further evidence for its involvement in desquamation-like processes","volume":"139","author":"Ekholm","year":"1998","journal-title":"Br J Dermatol"},{"key":"2025062423151823800_ljaf062-B28","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1046\/j.1523-1747.2003.12363.x","article-title":"Expression and localization of tissue kallikrein mRNAs in human epidermis and appendages","volume":"121","author":"Komatsu","year":"2003","journal-title":"J Invest Dermatol"},{"key":"2025062423151823800_ljaf062-B29","doi-asserted-by":"crossref","first-page":"3121","DOI":"10.1007\/s00018-010-0618-x","article-title":"The structure of the Klf4 DNA-binding domain links to self-renewal and macrophage differentiation","volume":"68","author":"Schuetz","year":"2011","journal-title":"Cell Mol Life Sci"},{"key":"2025062423151823800_ljaf062-B30","doi-asserted-by":"crossref","first-page":"4859","DOI":"10.1093\/nar\/gku134","article-title":"Structural basis for Klf4 \u00adrecognition of methylated DNA","volume":"42","author":"Liu","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2025062423151823800_ljaf062-B31","doi-asserted-by":"crossref","first-page":"2969","DOI":"10.1002\/stem.231","article-title":"Klf4 interacts directly with Oct4 and Sox2 to promote reprogramming","volume":"27","author":"Wei","year":"2009","journal-title":"Stem cells"},{"key":"2025062423151823800_ljaf062-B32","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1093\/bjd\/ljac029","article-title":"Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder","volume":"188","author":"Gong","year":"2023","journal-title":"Br J Dermatol"},{"key":"2025062423151823800_ljaf062-B33","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"}],"container-title":["British Journal of Dermatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bjd\/advance-article-pdf\/doi\/10.1093\/bjd\/ljaf062\/61988292\/ljaf062.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bjd\/article-pdf\/193\/1\/136\/61988292\/ljaf062.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bjd\/article-pdf\/193\/1\/136\/61988292\/ljaf062.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T03:15:26Z","timestamp":1750821326000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bjd\/article\/193\/1\/136\/8024203"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,19]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,2,19]]},"published-print":{"date-parts":[[2025,6,20]]}},"URL":"https:\/\/doi.org\/10.1093\/bjd\/ljaf062","relation":{},"ISSN":["0007-0963","1365-2133"],"issn-type":[{"value":"0007-0963","type":"print"},{"value":"1365-2133","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,7]]},"published":{"date-parts":[[2025,2,19]]}}}