{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T20:06:46Z","timestamp":1786133206178,"version":"build-2736575974"},"reference-count":55,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:p>\n                    Pierson syndrome is a congenital nephrotic syndrome with eye and neurologic defects caused by mutations in laminin\n                    <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                    2 (\n                    <jats:italic toggle=\"yes\">LAMB2<\/jats:italic>\n                    ), a major component of the glomerular basement membrane (GBM). Pathogenic missense mutations in human LAMB2 cluster in or near the laminin amino-terminal (LN) domain, a domain required for extracellular polymerization of laminin trimers and basement membrane scaffolding. Here, we investigated an LN domain missense mutation, LAMB2-S80R, which was discovered in a patient with Pierson syndrome and unusually late onset of proteinuria. Biochemical data indicated that this mutation impairs laminin polymerization, which we hypothesized to be the cause of the patient\u2019s nephrotic syndrome. Testing this hypothesis in genetically altered mice showed that the corresponding amino acid change (LAMB2-S83R) alone is not pathogenic. However, expression of LAMB2-S83R significantly increased the rate of progression to kidney failure in a\n                    <jats:italic toggle=\"yes\">Col4a3<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mouse model of autosomal recessive Alport syndrome and increased proteinuria in\n                    <jats:italic toggle=\"yes\">Col4a5<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    females that exhibit a mild form of X-linked Alport syndrome due to mosaic deposition of collagen\n                    <jats:italic toggle=\"yes\">\u03b1<\/jats:italic>\n                    3\n                    <jats:italic toggle=\"yes\">\u03b1<\/jats:italic>\n                    4\n                    <jats:italic toggle=\"yes\">\u03b1<\/jats:italic>\n                    5(IV) in the GBM. Collectively, these data show the pathogenicity of LAMB2-S80R and provide the first evidence of genetic modification of Alport phenotypes by variation in another GBM component. This finding could help explain the wide range of Alport syndrome onset and severity observed in patients with Alport syndrome, even for family members who share the same\n                    <jats:italic toggle=\"yes\">COL4<\/jats:italic>\n                    mutation. Our results also show the complexities of using model organisms to investigate genetic variants suspected of being pathogenic in humans.\n                  <\/jats:p>","DOI":"10.1681\/asn.2017090997","type":"journal-article","created":{"date-parts":[[2017,12,20]],"date-time":"2017-12-20T10:45:57Z","timestamp":1513766757000},"page":"949-960","source":"Crossref","is-referenced-by-count":36,"title":["Pathogenicity of a Human Laminin \u03b22 Mutation Revealed in Models of Alport Syndrome"],"prefix":"10.1681","volume":"29","author":[{"given":"Steven D.","family":"Funk","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond H.","family":"Bayer","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew F.","family":"Malone","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen K.","family":"McKee","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter D.","family":"Yurchenco","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey H.","family":"Miner","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,12,20]]},"reference":[{"key":"B1-20231016","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.1046\/j.1523-1755.1999.00785.x","article-title":"Renal basement membrane components.","volume":"56","author":"Miner","year":"1999","journal-title":"Kidney Int"},{"key":"B2-20231016","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.matbio.2003.10.006","article-title":"Basement membrane assembly, stability and activities observed through a developmental lens.","volume":"22","author":"Yurchenco","year":"2004","journal-title":"Matrix Biol"},{"key":"B3-20231016","doi-asserted-by":"crossref","first-page":"17286","DOI":"10.1016\/S0021-9258(19)85334-6","article-title":"Self-assembly and calcium-binding sites in laminin. A three-arm interaction model.","volume":"268","author":"Yurchenco","year":"1993","journal-title":"J Biol Chem"},{"key":"B4-20231016","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1681\/ASN.2004121139","article-title":"Building the glomerulus: A matricentric view.","volume":"16","author":"Miner","year":"2005","journal-title":"J Am Soc Nephrol"},{"key":"B5-20231016","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.ctm.2015.05.001","article-title":"Integrating activities of laminins that drive basement membrane assembly and function.","volume":"76","author":"Yurchenco","year":"2015","journal-title":"Curr Top Membr"},{"key":"B6-20231016","doi-asserted-by":"crossref","first-page":"2514","DOI":"10.1097\/01.ASN.0000141462.00630.76","article-title":"The molecular basis of Goodpasture and Alport syndromes: Beacons for the discovery of the collagen IV family.","volume":"15","author":"Hudson","year":"2004","journal-title":"J Am Soc Nephrol"},{"key":"B7-20231016","doi-asserted-by":"crossref","first-page":"e01149","DOI":"10.7554\/eLife.01149","article-title":"Nanoscale protein architecture of the kidney glomerular basement membrane.","volume":"2","author":"Suleiman","year":"2013","journal-title":"eLife"},{"key":"B8-20231016","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/ki.1992.269","article-title":"Distribution of the alpha 1 and alpha 2 chains of collagen IV and of collagens V and VI in Alport syndrome.","volume":"42","author":"Kashtan","year":"1992","journal-title":"Kidney Int"},{"key":"B9-20231016","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1002\/jemt.20567","article-title":"Nidogens-extracellular matrix linker molecules.","volume":"71","author":"Ho","year":"2008","journal-title":"Microsc Res Tech"},{"key":"B10-20231016","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1083\/jcb.200611152","article-title":"Linker molecules between laminins and dystroglycan ameliorate laminin-alpha2-deficient muscular dystrophy at all disease stages.","volume":"176","author":"Meinen","year":"2007","journal-title":"J Cell Biol"},{"key":"B11-20231016","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1681\/ASN.2013030233","article-title":"Global analysis reveals the complexity of the human glomerular extracellular matrix.","volume":"25","author":"Lennon","year":"2014","journal-title":"J Am Soc Nephrol"},{"key":"B12-20231016","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1007\/s00467-011-1785-1","article-title":"Glomerular basement membrane composition and the filtration barrier.","volume":"26","author":"Miner","year":"2011","journal-title":"Pediatr Nephrol"},{"key":"B13-20231016","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.yexcr.2012.02.031","article-title":"The glomerular basement membrane.","volume":"318","author":"Miner","year":"2012","journal-title":"Exp Cell Res"},{"key":"B14-20231016","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1002\/humu.21304","article-title":"Mutations in the human laminin beta2 (LAMB2) gene and the associated phenotypic spectrum.","volume":"31","author":"Matejas","year":"2010","journal-title":"Hum Mutat"},{"key":"B15-20231016","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1093\/hmg\/ddh284","article-title":"Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities.","volume":"13","author":"Zenker","year":"2004","journal-title":"Hum Mol Genet"},{"key":"B16-20231016","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1097\/00005792-199909000-00005","article-title":"Alport syndrome. An inherited disorder of renal, ocular, and cochlear basement membranes.","volume":"78","author":"Kashtan","year":"1999","journal-title":"Medicine (Baltimore)"},{"key":"B17-20231016","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/ki.2014.229","article-title":"The 2014 international workshop on Alport syndrome.","volume":"86","author":"Miner","year":"2014","journal-title":"Kidney Int"},{"key":"B18-20231016","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1038\/sj.ki.5001679","article-title":"Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2-associated disorders.","volume":"70","author":"Hasselbacher","year":"2006","journal-title":"Kidney Int"},{"key":"B19-20231016","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1681\/ASN.2010060632","article-title":"A missense LAMB2 mutation causes congenital nephrotic syndrome by impairing laminin secretion.","volume":"22","author":"Chen","year":"2011","journal-title":"J Am Soc 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inLamb2-\/- mice, implicating the glomerular basement membrane as an albumin barrier.","volume":"116","author":"Jarad","year":"2006","journal-title":"J Clin Invest"},{"key":"B24-20231016","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1242\/dev.02270","article-title":"Transgenic isolation of skeletal muscle and kidney defects in laminin beta2 mutant mice: Implications for Pierson syndrome.","volume":"133","author":"Miner","year":"2006","journal-title":"Development"},{"key":"B25-20231016","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/ng0895-400","article-title":"The renal glomerulus of mice lacking s-laminin\/laminin beta 2: Nephrosis despite molecular compensation by laminin beta 1.","volume":"10","author":"Noakes","year":"1995","journal-title":"Nat Genet"},{"key":"B26-20231016","doi-asserted-by":"crossref","first-page":"15348","DOI":"10.1073\/pnas.1108269108","article-title":"Forced expression of laminin beta1 in podocytes prevents nephrotic syndrome in mice lacking laminin beta2, a model for Pierson syndrome.","volume":"108","author":"Suh","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B27-20231016","doi-asserted-by":"crossref","first-page":"44270","DOI":"10.1074\/jbc.M112.418426","article-title":"Laminin network formation studied by reconstitution of ternary nodes in solution.","volume":"287","author":"Purvis","year":"2012","journal-title":"J Biol Chem"},{"key":"B28-20231016","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1083\/jcb.200501098","article-title":"Laminin-sulfatide binding initiates basement membrane assembly and enables receptor signaling in Schwann cells and fibroblasts.","volume":"169","author":"Li","year":"2005","journal-title":"J Cell Biol"},{"key":"B29-20231016","doi-asserted-by":"crossref","first-page":"21437","DOI":"10.1074\/jbc.M702963200","article-title":"Role of laminin terminal globular domains in basement membrane 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correlations in 127 patients in 11 large pedigrees, segregating one of three heterozygous mutations in the COL4A3\/ COL4A4 genes associated with familial haematuria and significant late progression to proteinuria and chronic kidney disease from focal segmental glomerulosclerosis.","volume":"24","author":"Pierides","year":"2009","journal-title":"Nephrol Dial Transplant"},{"key":"B40-20231016","doi-asserted-by":"crossref","first-page":"3004","DOI":"10.1681\/ASN.2007040444","article-title":"COL4A3\/COL4A4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy.","volume":"18","author":"Voskarides","year":"2007","journal-title":"J Am Soc Nephrol"},{"key":"B41-20231016","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1093\/ndt\/gfv325","article-title":"Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental 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knockout mice.","volume":"34","author":"Rubel","year":"2014","journal-title":"Matrix Biol"},{"key":"B48-20231016","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1007\/s00467-008-0934-7","article-title":"The R229Q mutation in NPHS2 may predispose to proteinuria in thin-basement-membrane nephropathy.","volume":"23","author":"Tonna","year":"2008","journal-title":"Pediatr Nephrol"},{"key":"B49-20231016","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aal4649","article-title":"Linker proteins restore basement membrane and correct LAMA2-related muscular dystrophy in mice.","volume":"9","author":"Reinhard","year":"2017","journal-title":"Sci Transl Med"},{"key":"B50-20231016","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/35095054","article-title":"An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular 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