{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:47:16Z","timestamp":1789984036777,"version":"4.0.1"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T00:00:00Z","timestamp":1647043200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T00:00:00Z","timestamp":1647043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["202860\/Z\/16\/Z"],"award-info":[{"award-number":["202860\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000291","name":"Kidney Research UK","doi-asserted-by":"crossref","award":["TF_007_20181122"],"award-info":[{"award-number":["TF_007_20181122"]}],"id":[{"id":"10.13039\/501100000291","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000881","name":"Lowe Syndrome Trust","doi-asserted-by":"publisher","award":["ML\/MU\/2012"],"award-info":[{"award-number":["ML\/MU\/2012"]}],"id":[{"id":"10.13039\/501100000881","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000881","name":"Lowe Syndrome Trust","doi-asserted-by":"publisher","award":["ML\/MU\/2016\/2017"],"award-info":[{"award-number":["ML\/MU\/2016\/2017"]}],"id":[{"id":"10.13039\/501100000881","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pediatr Nephrol"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract\n<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>CD151 is a cell-surface molecule of the tetraspanin family. Its lateral interaction with laminin-binding integrin \u02513\u03b21 is important for podocyte adhesion to the glomerular basement membrane (GBM). Deletion of <jats:italic>Cd151<\/jats:italic> in mice induces glomerular dysfunction, with proteinuria and associated focal glomerulosclerosis, disorganisation of GBM and tubular cystic dilation. Despite this, <jats:italic>CD151<\/jats:italic> is not routinely screened for in patients with nephrotic-range proteinuria. We aimed to better understand the relevance of <jats:italic>CD151<\/jats:italic> in human kidney disease.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Next-generation sequencing (NGS) was used to detect the variant in <jats:italic>CD151<\/jats:italic>. Electron and light microscopy were used to visualise the filtration barrier in the patient kidney biopsy, and immunoreactivity of patient red blood cells to anti-CD151\/MER2 antibodies was performed. Further validation of the <jats:italic>CD151<\/jats:italic> variant as disease-causing was performed in zebrafish using CRISPR-Cas9.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We report a young child with nail dystrophy and persistent urinary tract infections who was incidentally found to have nephrotic-range proteinuria. Through targeted NGS, a novel, homozygous truncating variant was identified in <jats:italic>CD151<\/jats:italic>, a gene rarely reported in patients with nephrotic syndrome. Electron microscopy imaging of patient kidney tissue\u00a0showed thickening of GBM and podocyte effacement. Immunofluorescence of patient kidney tissue demonstrated that CD151 was significantly reduced, and we did not detect immunoreactivity to CD151\/MER2 on patient red blood cells. CRISPR-Cas9 depletion of <jats:italic>cd151<\/jats:italic> in zebrafish caused proteinuria, which was rescued by injection of wild-type <jats:italic>CD151<\/jats:italic> mRNA, but not <jats:italic>CD151<\/jats:italic> mRNA containing the variant sequence.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our results indicate that a novel variant in <jats:italic>CD151<\/jats:italic> is associated with nephrotic-range proteinuria and microscopic haematuria and provides further evidence for a role of CD151 in glomerular disease. Our work highlights a functional testing pipeline for future analysis of patient genetic variants.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical abstract<\/jats:title>\n                <jats:p>A higher resolution version of the Graphical abstract is available as Supplementary information<\/jats:p>\n                \n              <\/jats:sec>","DOI":"10.1007\/s00467-022-05447-y","type":"journal-article","created":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T09:02:33Z","timestamp":1647075753000},"page":"3105-3115","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Basement membrane defects in CD151-associated glomerular disease"],"prefix":"10.1007","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2901-7677","authenticated-orcid":false,"given":"Richard W.","family":"Naylor","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4341-2967","authenticated-orcid":false,"given":"Elizabeth","family":"Watson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Williamson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Preston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0970-7275","authenticated-orcid":false,"given":"J Bernard","family":"Davenport","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8635-0997","authenticated-orcid":false,"given":"Nicole","family":"Thornton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9331-8143","authenticated-orcid":false,"given":"Martin","family":"Lowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6400-0227","authenticated-orcid":false,"given":"Rachel","family":"Lennon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,12]]},"reference":[{"key":"5447_CR1","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1016\/j.kint.2016.10.013","volume":"91","author":"A Bierzynska","year":"2017","unstructured":"Bierzynska A, McCarthy HJ, Soderquest K, Sen E et al (2017) Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management. Kidney Int 91:937\u2013947. https:\/\/doi.org\/10.1016\/j.kint.2016.10.013","journal-title":"Kidney Int"},{"key":"5447_CR2","doi-asserted-by":"publisher","first-page":"2217","DOI":"10.1182\/blood-2004-04-1512","volume":"104","author":"V Karamatic Crew","year":"2004","unstructured":"Karamatic Crew V, Burton N, Kagan A, Green CA et al (2004) CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin. Blood 104:2217\u20132223. https:\/\/doi.org\/10.1182\/blood-2004-04-1512","journal-title":"Blood"},{"key":"5447_CR3","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1007\/PL00000933","volume":"58","author":"C Boucheix","year":"2001","unstructured":"Boucheix C, Rubinstein E (2001) Tetraspanins. Cell Mol Life Sci 58:1189\u20131205. https:\/\/doi.org\/10.1007\/PL00000933","journal-title":"Cell Mol Life Sci"},{"key":"5447_CR4","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1046\/j.1523-1755.1998.00044.x","volume":"54","author":"W Kriz","year":"1998","unstructured":"Kriz W, Gretz N, Lemley KV (1998) Progression of glomerular diseases: is the podocyte the culprit? Kidney Int 54:687\u2013697. https:\/\/doi.org\/10.1046\/j.1523-1755.1998.00044.x","journal-title":"Kidney Int"},{"key":"5447_CR5","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1242\/jcs.115.6.1161","volume":"115","author":"LMT Sterk","year":"2002","unstructured":"Sterk LMT, Geuijen CAW, van den Berg JG, Claessen N et al (2002) Association of the tetraspanin CD151 with the laminin-binding integrins alpha3beta1, alpha6beta1, alpha6beta4 and alpha7beta1 in cells in culture and in vivo. J Cell Sci 115:1161\u20131173","journal-title":"J Cell Sci"},{"key":"5447_CR6","doi-asserted-by":"publisher","first-page":"2751","DOI":"10.1091\/mbc.9.10.2751","volume":"9","author":"RL Yauch","year":"1998","unstructured":"Yauch RL, Berditchevski F, Harler MB, Reichner J et al (1998) Highly stoichiometric, stable, and specific association of integrin alpha3beta1 with CD151 provides a major link to phosphatidylinositol 4-kinase, and may regulate cell migration. Mol Biol Cell 9:2751\u20132765. https:\/\/doi.org\/10.1091\/mbc.9.10.2751","journal-title":"Mol Biol Cell"},{"key":"5447_CR7","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1083\/jcb.200603073","volume":"175","author":"N Sachs","year":"2006","unstructured":"Sachs N, Kreft M, van den Bergh Weerman MA, Beynon AJ et al (2006) Kidney failure in mice lacking the tetraspanin CD151. J Cell Biol 175:33\u201339. https:\/\/doi.org\/10.1083\/jcb.200603073","journal-title":"J Cell Biol"},{"key":"5447_CR8","doi-asserted-by":"publisher","first-page":"927","DOI":"10.2353\/ajpath.2008.071149","volume":"173","author":"RM Baleato","year":"2008","unstructured":"Baleato RM, Guthrie PL, Gubler M-C, Ashman L et al (2008) Deletion of CD151 results in a strain-dependent glomerular disease due to severe alterations of the glomerular basement membrane. Am J Pathol 173:927\u2013937. https:\/\/doi.org\/10.2353\/ajpath.2008.071149","journal-title":"Am J Pathol"},{"key":"5447_CR9","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1172\/JCI58878","volume":"122","author":"N Sachs","year":"2012","unstructured":"Sachs N, Claessen N, Aten J, Kreft M et al (2012) Blood pressure influences end-stage renal disease of Cd151 knockout mice. J Clin Invest 122:348\u2013358. https:\/\/doi.org\/10.1172\/JCI58878","journal-title":"J Clin Invest"},{"key":"5447_CR10","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1172\/JCI61858","volume":"122","author":"A Pozzi","year":"2012","unstructured":"Pozzi A, Zent R (2012) Hold tight or you\u2019ll fall off: CD151 helps podocytes stick in high-pressure situations. J Clin Invest 122:13\u201316. https:\/\/doi.org\/10.1172\/JCI61858","journal-title":"J Clin Invest"},{"key":"5447_CR11","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405\u2013424. https:\/\/doi.org\/10.1038\/gim.2015.30","journal-title":"Genet Med"},{"key":"5447_CR12","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1002\/aja.1002030302","volume":"203","author":"CB Kimmel","year":"1995","unstructured":"Kimmel CB, Ballard WW, Kimmel SR, Ullman B et al (1995) Stages of embryonic development of the zebrafish. Dev Dyn 203:253\u2013310. https:\/\/doi.org\/10.1002\/aja.1002030302","journal-title":"Dev Dyn"},{"key":"5447_CR13","doi-asserted-by":"publisher","DOI":"10.1101\/2021.07.19.452884","author":"RWW Naylor","year":"2021","unstructured":"Naylor RWW, Lemarie E, Jackson-Crawford A, Davenport JB et al (2021) A novel nanoluciferase transgenic reporter to measure proteinuria in zebrafish. BioRxiv. https:\/\/doi.org\/10.1101\/2021.07.19.452884","journal-title":"BioRxiv"},{"key":"5447_CR14","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.devcel.2018.06.003","volume":"46","author":"RS Wu","year":"2018","unstructured":"Wu RS, Lam II, Clay H, Duong DN et al (2018) A rapid method for directed gene knockout for screening in G0 zebrafish. Dev Cell 46:112-125.e4. https:\/\/doi.org\/10.1016\/j.devcel.2018.06.003","journal-title":"Dev Cell"},{"key":"5447_CR15","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1038\/nprot.2015.053","volume":"10","author":"LA Kelley","year":"2015","unstructured":"Kelley LA, Mezulis S, Yates CM, Wass MN et al (2015) The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 10:845\u2013858. https:\/\/doi.org\/10.1038\/nprot.2015.053","journal-title":"Nat Protoc"},{"key":"5447_CR16","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.matbio.2017.11.003","volume":"66","author":"H Vahidnezhad","year":"2018","unstructured":"Vahidnezhad H, Youssefian L, Saeidian AH, Mahmoudi H et al (2018) Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy. Matrix Biol 66:22\u201333. https:\/\/doi.org\/10.1016\/j.matbio.2017.11.003","journal-title":"Matrix Biol"},{"key":"5447_CR17","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1046\/j.1523-1755.2002.00527.x","volume":"62","author":"IJ Ramage","year":"2002","unstructured":"Ramage IJ, Howatson AG, McColl JH, Maxwell H et al (2002) Glomerular basement membrane thickness in children: a stereologic assessment. Kidney Int 62:895\u2013900. https:\/\/doi.org\/10.1046\/j.1523-1755.2002.00527.x","journal-title":"Kidney Int"},{"key":"5447_CR18","doi-asserted-by":"publisher","first-page":"e45286","DOI":"10.1371\/journal.pone.0045286","volume":"7","author":"K Ichimura","year":"2012","unstructured":"Ichimura K, Bubenshchikova E, Powell R, Fukuyo Y et al (2012) A comparative analysis of glomerulus development in the pronephros of medaka and zebrafish. PLoS ONE 7:e45286. https:\/\/doi.org\/10.1371\/journal.pone.0045286","journal-title":"PLoS ONE"},{"key":"5447_CR19","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/B978-0-12-384892-5.00009-8","volume":"100","author":"IA Drummond","year":"2010","unstructured":"Drummond IA, Davidson AJ (2010) Zebrafish kidney development. Methods Cell Biol 100:233\u2013260. https:\/\/doi.org\/10.1016\/B978-0-12-384892-5.00009-8","journal-title":"Methods Cell Biol"},{"key":"5447_CR20","unstructured":"Thisse B, Thisse C (2004) Fast Release Clones: A High Throughput Expression Analysis. ZFIN"},{"key":"5447_CR21","doi-asserted-by":"publisher","first-page":"F531","DOI":"10.1152\/ajprenal.00247.2015","volume":"309","author":"SA Rider","year":"2015","unstructured":"Rider SA, Mullins LJ, Verdon RF, MaCrae CA et al (2015) Renin expression in developing zebrafish is associated with angiogenesis and requires the Notch pathway and endothelium. Am J Physiol Renal Physiol 309:F531\u2013F539. https:\/\/doi.org\/10.1152\/ajprenal.00247.2015","journal-title":"Am J Physiol Renal Physiol"},{"key":"5447_CR22","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1038\/s42255-020-0204-y","volume":"2","author":"L Butt","year":"2020","unstructured":"Butt L, Unnersj\u00f6-Jess D, H\u00f6hne M, Edwards A et al (2020) A molecular mechanism explaining albuminuria in kidney disease. Nat Metab 2:461\u2013474. https:\/\/doi.org\/10.1038\/s42255-020-0204-y","journal-title":"Nat Metab"},{"key":"5447_CR23","doi-asserted-by":"publisher","first-page":"2958","DOI":"10.1073\/pnas.1616457114","volume":"114","author":"MG Lawrence","year":"2017","unstructured":"Lawrence MG, Altenburg MK, Sanford R, Willett JD et al (2017) Permeation of macromolecules into the renal glomerular basement membrane and capture by the tubules. Proc Natl Acad Sci USA 114:2958\u20132963. https:\/\/doi.org\/10.1073\/pnas.1616457114","journal-title":"Proc Natl Acad Sci USA"},{"key":"5447_CR24","doi-asserted-by":"publisher","first-page":"41165","DOI":"10.1074\/jbc.M104041200","volume":"276","author":"F Berditchevski","year":"2001","unstructured":"Berditchevski F, Gilbert E, Griffiths MR, Fitter S et al (2001) Analysis of the CD151-alpha3beta1 integrin and CD151-tetraspanin interactions by mutagenesis. J Biol Chem 276:41165\u201341174. https:\/\/doi.org\/10.1074\/jbc.M104041200","journal-title":"J Biol Chem"},{"key":"5447_CR25","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1038\/nsmb.1550","volume":"16","author":"S Brogna","year":"2009","unstructured":"Brogna S, Wen J (2009) Nonsense-mediated mRNA decay (NMD) mechanisms. Nat Struct Mol Biol 16:107\u2013113. https:\/\/doi.org\/10.1038\/nsmb.1550","journal-title":"Nat Struct Mol Biol"}],"container-title":["Pediatric Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00467-022-05447-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00467-022-05447-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00467-022-05447-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,21]],"date-time":"2022-10-21T08:22:55Z","timestamp":1666340575000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00467-022-05447-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,12]]},"references-count":25,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["5447"],"URL":"https:\/\/doi.org\/10.1007\/s00467-022-05447-y","relation":{},"ISSN":["0931-041X","1432-198X"],"issn-type":[{"value":"0931-041X","type":"print"},{"value":"1432-198X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,12]]},"assertion":[{"value":"27 August 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 January 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 January 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no conflicts of interests and have nothing to disclose.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interests"}}]}}