{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T04:24:22Z","timestamp":1772511862499,"version":"3.50.1"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2024,3,17]],"date-time":"2024-03-17T00:00:00Z","timestamp":1710633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science Foundation Ireland (SFI) COVID-19","award":["20\/COV\/0312"],"award-info":[{"award-number":["20\/COV\/0312"]}]},{"DOI":"10.13039\/501100001602","name":"SFI","doi-asserted-by":"publisher","award":["Eye-D-21\/SPP\/3732"],"award-info":[{"award-number":["Eye-D-21\/SPP\/3732"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001588","name":"Enterprise Ireland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001588","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002081","name":"Irish Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002081","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001602","name":"SFI","doi-asserted-by":"publisher","award":["21\/RC\/10294_P2"],"award-info":[{"award-number":["21\/RC\/10294_P2"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Regional Development"},{"DOI":"10.13039\/100010663","name":"European Research Council","doi-asserted-by":"publisher","award":["864522"],"award-info":[{"award-number":["864522"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,6,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Claudin-25 (CLDN-25), also known as Claudin containing domain 1, is an uncharacterized claudin family member. It has less conserved amino acid sequences when compared to other claudins. It also has a very broad tissue expression profile and there is currently a lack of functional information from murine knockout models. Here, we report a de novo missense heterozygous variant in CLDN25 (c. 745G&amp;gt;C, p. A249P) found in a patient diagnosed with Pelizaeus-Merzbacher-like leukodystrophy and presenting with symptoms such as delayed motor development, several episodes of tonic absent seizures and generalized dystonia. The variant protein does not localize to the cell-cell borders where it would normally be expected to be expressed. Amino acid position 249 is located 4 amino acids from the C-terminal end of the protein where most claudin family members have a conserved binding motif for the key scaffolding protein ZO-1. However, CLDN-25 does not contain this motif. Here, we show that the C-terminal end of CLDN-25 is required for its junctional localization in a ZO-1 independent manner. The A249P mutant protein as well as a deletion mutant lacking its last 5 C-terminal amino acids also failed to localize to the cell-cell border in vitro. Intriguingly, cellular knockout of CLDN25, in vitro, appeared to increase the integrity of the tight junction between 2 contacting cells, while driving highly unusual increased movement of solutes between cells. We propose that the barrier function of CLDN-25 is akin to a decoy claudin, whereby decreasing its expression in \u201cleaky\u201d epithelial cells and endothelial cells will drive dynamic changes in the adhesion and interaction capacity of cell-cell contact points. While it remains unclear how this de novo CLDN-25 mutant induces leukodystrophy, our findings strongly suggest that this mutation induces haploinsufficiency of CLDN-25. Elucidating the function of this uncharacterized claudin protein will lead to a better understanding of the role of claudin proteins in health and disease.<\/jats:p>","DOI":"10.1093\/hmg\/ddae038","type":"journal-article","created":{"date-parts":[[2024,3,17]],"date-time":"2024-03-17T14:04:48Z","timestamp":1710684288000},"page":"1055-1063","source":"Crossref","is-referenced-by-count":4,"title":["A loss of function mutation in <i>CLDN25<\/i> causing Pelizaeus-Merzbacher-like leukodystrophy"],"prefix":"10.1093","volume":"33","author":[{"given":"Yosuke","family":"Hashimoto","sequence":"first","affiliation":[{"name":"Smurfit Institute of Genetics, Trinity College Dublin , D02 VF25, Dublin , Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claude","family":"Besmond","sequence":"additional","affiliation":[{"name":"INSERM UMR1163 , Institut Imagine, , F-75015, Paris , France"},{"name":"Paris University , Institut Imagine, , F-75015, Paris , France"},{"name":"Clinical Genetics Department, Necker Hospital, APHP Centre-Paris University , F-75015, Paris , France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalie","family":"Boddaert","sequence":"additional","affiliation":[{"name":"INSERM UMR1163 , Institut Imagine, , F-75015, Paris , France"},{"name":"Paris University , Institut Imagine, , F-75015, Paris , France"},{"name":"Department of Pediatric Radiology, Hospital Necker Enfants Malades , F-75015, Paris , France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arnold","family":"Munnich","sequence":"additional","affiliation":[{"name":"INSERM UMR1163 , Institut Imagine, , F-75015, Paris , France"},{"name":"Paris University , Institut Imagine, , F-75015, Paris , France"},{"name":"Clinical Genetics Department, Necker Hospital, APHP Centre-Paris University , F-75015, Paris , France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Campbell","sequence":"additional","affiliation":[{"name":"Smurfit Institute of Genetics, Trinity College Dublin , D02 VF25, Dublin , Ireland"},{"name":"FutureNeuro , Science Foundation Ireland Research Centre for Chronic and Rare Neurological Diseases, Royal College of Surgeons in Ireland, , Dublin , Ireland"},{"name":"University of Medicine and Health Sciences , Science Foundation Ireland Research Centre for Chronic and Rare Neurological Diseases, Royal College of Surgeons in Ireland, , Dublin , Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,3,17]]},"reference":[{"key":"2024060606010855400_ref1","doi-asserted-by":"crossref","first-page":"e14","DOI":"10.1017\/S1462399408000677","article-title":"The molecular and cellular defects underlying Pelizaeus-Merzbacher disease","volume":"10","author":"Woodward","year":"2008","journal-title":"Expert Rev Mol Med"},{"key":"2024060606010855400_ref2","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1086\/422763","article-title":"Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease","volume":"75","author":"Uhlenberg","year":"2004","journal-title":"Am J Hum Genet"},{"key":"2024060606010855400_ref3","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.ajhg.2008.05.016","article-title":"Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy","volume":"83","author":"Magen","year":"2008","journal-title":"Am J Hum Genet"},{"key":"2024060606010855400_ref4","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1007\/s00439-019-02077-7","article-title":"Compound heterozygous mutations in SNAP29 is associated with Pelizaeus-Merzbacher-like disorder (PMLD)","volume":"138","author":"Llaci","year":"2019","journal-title":"Hum Genet"},{"key":"2024060606010855400_ref5","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1038\/ejhg.2017.119","article-title":"Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus-Merzbacher disease","volume":"25","author":"Nafisinia","year":"2017","journal-title":"Eur J Hum Genet"},{"key":"2024060606010855400_ref6","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.ajhg.2010.10.016","article-title":"Pelizaeus-Merzbacher-like disease caused by AIMP1\/p43 homozygous mutation","volume":"87","author":"Feinstein","year":"2010","journal-title":"Am J Hum Genet"},{"key":"2024060606010855400_ref7","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/nature25739","article-title":"A molecular atlas of cell types and zonation in the brain 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