{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:01:32Z","timestamp":1787022092242,"version":"build-2736575974"},"reference-count":60,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T00:00:00Z","timestamp":1634688000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tunisian Ministry of Public Health"},{"DOI":"10.13039\/100010450","name":"Ministry of Higher Education and Scientific Research","doi-asserted-by":"publisher","award":["LR20IPT05"],"award-info":[{"award-number":["LR20IPT05"]}],"id":[{"id":"10.13039\/100010450","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Commission Program-Europe Aid"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Erythrokeratodermia variabilis (EKV) is a rare disorder of cornification usually associated with dominant mutations in the\n                    <jats:italic>GJB3<\/jats:italic>\n                    and\n                    <jats:italic>GJB4<\/jats:italic>\n                    genes encoding connexins (Cx)31 and 30.3. Genetic heterogeneity of EKV has already been suggested. We investigated at the clinical and genetic level a consanguineous Tunisian family with 2 sisters presenting an autosomal recessive form of EKV to better characterize this disease. Mutational analysis initially screened the connexin genes and Whole-exome sequencing (WES) was performed to identify the molecular aetiology of the particular EKV phenotype in the proband. Migratory shaped erythematous areas are the initial presenting sign followed by relatively stable hyperkeratotic plaques are the two predominates characteristics in both patients. However, remarkable variability of morphological and dominating features of the disease were observed between patients. In particular, the younger sister (proband) exhibited ichthyosiform-like appearance suggesting Autosomal Recessive Congenital Ichthyosis (ARCI) condition. No causative mutations were detected in the\n                    <jats:italic>GJB3<\/jats:italic>\n                    and\n                    <jats:italic>GJB4<\/jats:italic>\n                    genes. WES results revealed a novel missense homozygous mutation in\n                    <jats:italic>NIPAL4<\/jats:italic>\n                    gene (c.835C&gt;G, p.Pro279Ala) in both patients. This variant is predicted to be likely pathogenic. In addition,\n                    <jats:italic>in silico<\/jats:italic>\n                    analysis of the mutated 3D domain structure predicted that this variant would result in NIPA4 protein destabilization and Mg\n                    <jats:sup>2+<\/jats:sup>\n                    transport perturbation, pointing out the potential role of\n                    <jats:italic>NIPAL4<\/jats:italic>\n                    gene in the development and maintenance of the barrier function of the epidermis. Taken togheter, these results expand the clinical phenotype associated with\n                    <jats:italic>NIPAL4<\/jats:italic>\n                    mutation and reinforce our hypothesis of\n                    <jats:italic>NIPAL4<\/jats:italic>\n                    as the main candidate gene for the EKV-like ARCI phenotype.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0258777","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T23:46:19Z","timestamp":1634773579000},"page":"e0258777","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis\u2014Like Autosomal Recessive Congenital Ichthyosis"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4656-2661","authenticated-orcid":true,"given":"Cherine","family":"Charfeddine","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Laroussi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahma","family":"Mkaouar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raja","family":"Jouini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olfa","family":"Khayat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aladin","family":"Redissi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amor","family":"Mosbah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamza","family":"Dallali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achraf","family":"Chedly Debbiche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anissa","family":"Zaouak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami","family":"Fenniche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Abdelhak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houda","family":"Hammami-Ghorbel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,10,20]]},"reference":[{"key":"pone.0258777.ref001","article-title":"The Molecular Pathology of Progressive Symmetric Erythrokeratoderma: A Frameshift Mutation in the Loricrin Gene and Perturbations in the Cornified Cell Envelope","author":"A Ishida-Yamamoto","year":"1997","journal-title":"Am J Hum Genet"},{"key":"pone.0258777.ref002","first-page":"610","article-title":"CEDNIK syndrome results from loss-of-function mutations in SNAP29","volume":"164","author":"D Fuchs-Telem","year":"2011","journal-title":"Br J Dermatol"},{"key":"pone.0258777.ref003","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/3840","article-title":"Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis","volume":"20","author":"G Richard","year":"1998","journal-title":"Nat Genet"},{"key":"pone.0258777.ref004","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1111\/j.1365-2133.2005.06610.x","article-title":"A new, recurrent mutation of GJB3 (Cx31) in erythrokeratodermia variabilis","volume":"152","author":"SM Morley","year":"2005","journal-title":"Br J Dermatol"},{"key":"pone.0258777.ref005","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1046\/j.1365-2133.2000.04001.x","article-title":"Towards a better classification of erythrokeratodermias","volume":"143","author":"D. 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