{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T10:01:45Z","timestamp":1753869705816,"version":"3.41.2"},"reference-count":19,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,3,15]],"date-time":"2024-03-15T00:00:00Z","timestamp":1710460800000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Although proteinuria is long recognized as an independent risk factor for progressive chronic kidney diseases, not all forms of proteinuria are detrimental to kidney function, one of which is isolated proteinuria caused by <jats:italic>cubilin<\/jats:italic> (<jats:italic>CUBN)<\/jats:italic>\u2010specific mutations. <jats:italic>CUBN<\/jats:italic> encodes an endocytic receptor, initially found to be responsible for the Imerslund\u2013Gr\u00e4sbeck syndrome (IGS; OMIM #261100) characterized by a combined phenotype of megaloblastic anemia and proteinuria.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>After analyzing their clinical and pathological characterizations, next\u2010generation sequencing for renal disease genes or whole\u2010exome sequencing (WES) was performed on four patients with non\u2010progressive isolated proteinuria. <jats:italic>CUBN<\/jats:italic> biallelic pathogenic variants were identified and further analyzed by cDNA\u2010PCR sequencing, immunohistochemistry, minigene assay, and multiple in silico prediction tools, including 3D protein modeling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, we present four patients with isolated proteinuria caused by <jats:italic>CUBN<\/jats:italic> C\u2010terminal biallelic pathogenic variants, all of which showed no typical IGS symptoms, such as anemia and vitamin B12 deficiency. Their urine protein levels fluctuated between +~++ and estimated glomerular filtration rate (eGFR) were normal or slightly higher. Mild mesangial hypercellularity was found in three children's renal biopsies. A homozygous splice\u2010site variant of <jats:italic>CUBN<\/jats:italic> (c.6821+3 (IVS44) A&gt;G) was proven to result in the exon 44 skipping and premature translation termination by cDNA sequencing and immunohistochemistry. Compound heterozygous mutations were identified among the other three children, including another novel splice\u2010site variant (c.10764+1 (IVS66) G&gt;A) causing the retention of first 4 nucleotides in intron 66 by minigene assay, two unreported missense mutations (c.4907G&gt;A (p.R1636Q); c. 9095 A&gt;G (p.Y3032C)), and two reported missense mutations in China (c.8938G&gt;A (p.D2980N); c. 9287T&gt;C (p.L3096P)), locating behind the vitamin B12\u2010binding domain, affecting CUB11, CUB16, CUB22, CUB23, and CUB27 domains, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results demonstrate that above <jats:italic>CUBN<\/jats:italic> mutations may cause non\u2010progressive and isolated proteinuria, expanding the variant spectrum of <jats:italic>CUBN<\/jats:italic> and benefiting our understanding of proteinuria and renal function.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.2353","type":"journal-article","created":{"date-parts":[[2024,3,16]],"date-time":"2024-03-16T06:41:13Z","timestamp":1710571273000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of novel pathogenic variants of <i>CUBN<\/i> in patients with isolated proteinuria"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1836-1387","authenticated-orcid":false,"given":"Huihui","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Nephrology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Center) Tongji Medical College, Huazhong University of Science &amp; Technology  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lanfen","family":"He","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Center) Tongji Medical College, Huazhong University of Science &amp; Technology  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongjian","family":"Gong","sequence":"additional","affiliation":[{"name":"Clinical Research Center, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Center) Tongji Medical College, Huazhong University of Science &amp; Technology  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunhui","family":"Wan","sequence":"additional","affiliation":[{"name":"Precision Medical Center, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Center) Tongji Medical College, Huazhong University of Science &amp; Technology  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juanjuan","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Center) Tongji Medical College, Huazhong University of Science &amp; Technology  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panli","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Center) Tongji Medical College, Huazhong University of Science &amp; Technology  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaowen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Center) Tongji Medical College, Huazhong University of Science &amp; Technology  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,3,15]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-018-4783-z"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/6831"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010050492"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI129937"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010060598"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfs565"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfab285"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.13335"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-022-03706-y"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-007-0571-3"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12882-019-1474-z"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V91.10.3593"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.2.405.014k16_405_409"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07468-4"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2011040337"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfr794"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00484.2013"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2017111197"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12882-021-02654-x"}],"container-title":["Molecular Genetics &amp; 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