{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:54:53Z","timestamp":1753890893902,"version":"3.41.2"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T00:00:00Z","timestamp":1747008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Nail-patella syndrome (NPS) is an autosomal dominant disorder caused by the variants of the <jats:italic>LMX1B<\/jats:italic> gene, affecting several systems, including musculoskeletal, renal, and ocular systems. Despite the well-established genetic basis, the complicated relationship between genotype and phenotype still remains unclear. This study aimed to identify the genetic cause of NPS in a Chinese family and elucidate its potential contribution to the disease\u2019s phenotypic spectrum.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Clinical data and peripheral blood samples were collected from the affected family. Whole-exome sequencing (WES) was conducted to identify potential pathogenic variants, followed by Sanger sequencing to validate the candidate variant. Bioinformatic tools were employed to predict the 3D structure alterations and pathogenicity of the variant. Wild-type and mutant <jats:italic>LMX1B<\/jats:italic> overexpression plasmids were constructed to investigate the functional consequences of the variant. Western blotting and immunofluorescence were conducted to measure the expression and localization of the protein.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The proband presented with clinical manifestations, including nail malformation, patella dysplasia, restricted elbow movement, and pes planus. Both his mother and sister exhibited symptoms related to the skeletal system. WES identified a novel c.812G&amp;gt;C (p.R271T) variant in the affected family members. Bioinformatic analyses revealed structural modification in the protein and predicted functional impairment. Western blotting showed no significant difference in the expression level between wild-type and mutant protein. However, immunofluorescence demonstrated distinct changes in the subcellular localization of c.812G&amp;gt;C mutant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>NPS is a rare multisystem disorder with variable clinical presentations. In this family, the skeletal system was mainly involved with variations among different members. Our study identified a novel c.812G &amp;gt; c variant in the <jats:italic>LMX1B<\/jats:italic> gene, changing the nuclear localization of the protein.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2025.1574076","type":"journal-article","created":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T04:13:07Z","timestamp":1747023187000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of a novel missense variant in the LMX1B gene associated with nail-patella syndrome in a Chinese family"],"prefix":"10.3389","volume":"16","author":[{"given":"Qian","family":"Sun","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaqiong","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guanghao","family":"Su","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaodong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1053\/j.ajkd.2017.09.023","article-title":"LMX1B-Associated nephropathy with type III collagen deposition in the glomerular and tubular basement membranes","volume":"72","author":"Andeen","year":"2017","journal-title":"Am. J. Kidney Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/s41592-023-02086-5","article-title":"Accurate prediction of protein-nucleic acid complexes using RoseTTAFoldNA","volume":"21","author":"Baek","year":"2024","journal-title":"Nat. Methods"},{"key":"B3","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1038\/sj.ejhg.5201446","article-title":"Genotype-phenotype studies in nail-patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy","volume":"13","author":"Bongers","year":"","journal-title":"Eur. J. Hum. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1038\/sj.ejhg.5201446","article-title":"Genotype\u2013phenotype studies in nail-patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy","volume":"13","author":"Bongers","year":"","journal-title":"Eur. J. Hum. Genet."},{"key":"B5","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1002\/dvdy.695","article-title":"The limb dorsoventral axis: Lmx1b's role in development, pathology, evolution, and regeneration","volume":"253","author":"Castilla-Ibeas","year":"2024","journal-title":"Dev. Dyn."},{"key":"B6","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1038\/ng0598-51","article-title":"Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome","volume":"19","author":"Chen","year":"1998","journal-title":"Nat. Genet."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1093\/hmg\/9.7.1067","article-title":"LMX1B transactivation and expression in nail-patella syndrome","volume":"9","author":"Dreyer","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1093\/hmg\/9.7.1067","article-title":"LMX1B transactivation and expression in nail-patella syndrome","volume":"9","author":"Dreyer","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/ng0598-47","article-title":"Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome","volume":"19","author":"Dreyer","year":"1998","journal-title":"Nat. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1007\/s11248-007-9118-7","article-title":"Renal phenotype in heterozygous Lmx1b knockout mice (Lmx1b+\/-) after unilateral nephrectomy","volume":"16","author":"Endele","year":"2007","journal-title":"Transgenic Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2165","DOI":"10.1101\/gad.6.11.2165","article-title":"Synergistic activation of the insulin gene by a LIM-homeo domain protein and a basic helix-loop-helix protein: building a functional insulin minienhancer complex","volume":"6","author":"German","year":"1992","journal-title":"Genes. and Dev."},{"key":"B12","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/ejhg.2015.77","article-title":"Nail\u2013Patella Syndrome: clinical and molecular data in 55 families raising the hypothesis of a genetic heterogeneity","volume":"24","author":"Ghoumid","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1097\/01241398-199111000-00007","article-title":"Nail patella syndrome: a review of 44 orthopaedic patients","volume":"11","author":"Guidera","year":"1991","journal-title":"J. Pediatr. Orthop."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.1007\/s00467-016-3462-x","article-title":"Spectrum of LMX1B mutations: from nail\u2013patella syndrome to isolated nephropathy","volume":"32","author":"Harita","year":"2016","journal-title":"Pediatr. Nephrol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"5533","DOI":"10.1038\/s41467-021-25844-5","article-title":"Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity","volume":"12","author":"Haro","year":"2021","journal-title":"Nat. Commun."},{"key":"B16","doi-asserted-by":"publisher","first-page":"329","DOI":"10.3928\/0147-7447-20030301-16","article-title":"Bilateral hip dislocation and pubic diastasis in familial nail-patella syndrome","volume":"26","author":"Jacofsky","year":"2003","journal-title":"Orthopedics"},{"key":"B17","doi-asserted-by":"publisher","first-page":"920","DOI":"10.1038\/nrm1499","article-title":"The LIM domain: from the cytoskeleton to the nucleus","volume":"5","author":"Kadrmas","year":"2004","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2345","DOI":"10.1007\/s00467-008-0836-8","article-title":"Kidney disease in nail-patella syndrome","volume":"24","author":"Lemley","year":"2009","journal-title":"Pediatr. Nephrol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/j.bone.2008.04.025","article-title":"A novel mutation in LMX1B gene causes nail-patella syndrome in a large Chinese family","volume":"43","author":"Lin","year":"2008","journal-title":"Bone"},{"key":"B20","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1159\/000527234","article-title":"Nail-patella syndrome and glaucoma: a case report and review of the literature","volume":"13","author":"Pallozzi Lavorante","year":"2022","journal-title":"Case Rep. Ophthalmol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"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","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/0092-8674(95)90103-5","article-title":"Induction of the LIM homeobox gene Lmx1 by WNT7a establishes dorsoventral pattern in the vertebrate limb","volume":"83","author":"Riddle","year":"1995","journal-title":"Cell."},{"key":"B23","doi-asserted-by":"publisher","first-page":"988996","DOI":"10.3389\/fmolb.2022.988996","article-title":"pyDockDNA: a new web server for energy-based protein-DNA docking and scoring","volume":"9","author":"Rodr\u00edguez-Lumbreras","year":"2022","journal-title":"Front. Mol. Biosci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1203\/01.Pdr.0000157674.63621.2c","article-title":"Functional characterization of LMX1B mutations associated with nail-patella syndrome","volume":"57","author":"Sato","year":"2005","journal-title":"Pediatr. Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1136\/jmg.40.3.153","article-title":"Nail patella syndrome: a review of the phenotype aided by developmental biology","volume":"40","author":"Sweeney","year":"2003","journal-title":"J. Med. Genet."},{"key":"B26","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1038\/378716a0","article-title":"Dorsal cell fate specified by chick Lmx1 during vertebrate limb development","volume":"378","author":"Vogel","year":"1995","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic acids Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1111\/bjd.13051","article-title":"Biochemical properties of the recurrent LMX1b truncated mutant carried in a Taiwanese family with nail-patella syndrome","volume":"171","author":"Wang","year":"2014","journal-title":"Br. J. Dermatology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1007\/s00424-017-2013-z","article-title":"Nail-patella syndrome","volume":"469","author":"Witzgall","year":"2017","journal-title":"Pfl\u00fcgers Archiv - Eur. J. Physiology"},{"key":"B30","doi-asserted-by":"publisher","first-page":"285","DOI":"10.3109\/10799893.2012.727832","article-title":"The signaling pathways of LMX1B and its role in glomerulosclerosis","volume":"32","author":"Zhou","year":"2012","journal-title":"J. Recept. Signal Transduct."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1574076\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T04:13:08Z","timestamp":1747023188000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1574076\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,12]]},"references-count":30,"alternative-id":["10.3389\/fgene.2025.1574076"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2025.1574076","relation":{},"ISSN":["1664-8021"],"issn-type":[{"type":"electronic","value":"1664-8021"}],"subject":[],"published":{"date-parts":[[2025,5,12]]},"article-number":"1574076"}}