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Recent reports describing <jats:italic>NUP93<\/jats:italic> variants suggest these could be a significant cause of paediatric onset SRNS. We report <jats:italic>NUP93<\/jats:italic> cases in the UK and demonstrate in vivo functional effects of <jats:italic>Nup93<\/jats:italic> depletion in a fly (<jats:italic>Drosophila melanogaster)<\/jats:italic> nephrocyte model.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Three hundred thirty-seven paediatric SRNS patients from the National cohort of patients with Nephrotic Syndrome (NephroS) were whole exome and\/or whole genome sequenced. Patients were screened for over 70 genes known to be associated with Nephrotic Syndrome (NS). <jats:italic>D. melanogaster Nup93<\/jats:italic> knockdown was achieved by RNA interference using nephrocyte-restricted drivers.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Six novel homozygous and compound heterozygous <jats:italic>NUP93<\/jats:italic> variants were detected in 3 sporadic and 2 familial paediatric onset SRNS characterised histologically by focal segmental glomerulosclerosis (FSGS) and progressing to kidney failure by 12\u00a0months from clinical diagnosis.<\/jats:p>\n                <jats:p>Silencing of the two orthologs of human <jats:italic>NUP93<\/jats:italic> expressed in <jats:italic>D. melanogaster<\/jats:italic>, <jats:italic>Nup93-1<\/jats:italic>, and <jats:italic>Nup93-2<\/jats:italic> resulted in significant signal reduction of up to 82% in adult pericardial nephrocytes with concomitant disruption of NPC protein expression. Additionally, nephrocyte morphology was highly abnormal in <jats:italic>Nup93-1<\/jats:italic> and <jats:italic>Nup93-2<\/jats:italic> silenced flies surviving to adulthood.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>We expand the spectrum of <jats:italic>NUP93<\/jats:italic> variants detected in paediatric onset SRNS and demonstrate its incidence within a national cohort. Silencing of either <jats:italic>D. melanogaster Nup93<\/jats:italic> ortholog caused a severe nephrocyte phenotype, signaling an important role for the nucleoporin complex in podocyte biology.<\/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\n<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00467-022-05440-5","type":"journal-article","created":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T19:02:42Z","timestamp":1645729362000},"page":"2643-2656","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Exploring the relevance of NUP93 variants in steroid-resistant nephrotic syndrome using next generation sequencing and a fly kidney model"],"prefix":"10.1007","volume":"37","author":[{"given":"Agnieszka","family":"Bierzynska","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine","family":"Bull","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Miellet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip","family":"Dean","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris","family":"Neal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Colby","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hugh J.","family":"McCarthy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shivaram","family":"Hegde","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manish D.","family":"Sinha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"Bugarin Diz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen","family":"Stirrups","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karyn","family":"Megy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rutendo","family":"Mapeta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris","family":"Penkett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Marsh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalie","family":"Forrester","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maryam","family":"Afzal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"Stark","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"NIHR","family":"BioResource","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maggie","family":"Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gavin I.","family":"Welsh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ania B.","family":"Koziell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul S.","family":"Hartley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9808-4518","authenticated-orcid":false,"given":"Moin A.","family":"Saleem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,2,24]]},"reference":[{"key":"5440_CR1","doi-asserted-by":"publisher","unstructured":"Kabachinski G, Schwartz TU (2015) The nuclear pore complex\u2013structure and function at a glance. 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