{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T13:34:13Z","timestamp":1758893653943,"version":"3.41.2"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T00:00:00Z","timestamp":1661385600000},"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. Pediatr."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Focal segmental glomerulosclerosis (FSGS) is a histopathological diagnosis of the sclerosis of glomeruli and the damage to renal podocytes. FSGS affects the filtration function of the kidneys and results in nephrotic syndrome (NS) in children and adults. FSGS is a clinically and genetically heterogeneous disorder. FSGS-1 [OMIM #603278] is one of the progressive hereditary renal diseases. It is caused by heterozygous variants of the<jats:italic>actinin alpha 4<\/jats:italic>(<jats:italic>ACTN4<\/jats:italic>) [OMIM*604638] gene on chromosome 19q13.2 in a dominant inheritance (AD) manner. With the recent development of whole-exome sequencing (WES), 22 (including our case) pathogenic or likely pathogenic variants have been identified in<jats:italic>ACTN4<\/jats:italic>gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>Case presentation<\/jats:title><jats:p>We reported a 17-year-old Chinese girl who was hospitalized with foamy urine, nausea and vomiting. Laboratory tests revealed increased levels of serum creatinine and urea nitrogen. Ultrasonography demonstrated bilaterally reduced size of kidneys. The primary diagnoses were NS and chronic kidney disease stage 5 (CKD5). The hemodialysis was initiated in 48 h after admission. After 4 months of treatment, the patient received an allogeneic kidney transplantation from her father. A novel heterozygous missense variant c.494C &amp;gt; T (p.A165V) in the<jats:italic>ACTN4<\/jats:italic>gene was found by WES in the patient. This variant was confirmed by Sanger sequencing. The computational simulation of the stability of mutant protein (p.A165V) was decreased. Interatomic interactions of the p.A165V site were increased, and it might be associated with the increased ubiquitylation in the vicinity of the mutant site.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>As per the guidelines of the American College of Medical Genetics and Genomics for interpreting sequence variants, the novel heterozygous missense variant was pathogenic (PS2 + PM1 + PM2 + PP3 + PP4). It should be noted that the early onset of severe proteinuria with a poor prognosis is an important and universal symptom for most genetic FSGS. If necessary, genetic screening is recommended.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fped.2022.930258","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T06:36:51Z","timestamp":1661409411000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Case report and literature review: A de novo pathogenic missense variant in ACTN4 gene caused rapid progression to end-stage renal disease"],"prefix":"10.3389","volume":"10","author":[{"given":"Zhechi","family":"He","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenqing","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianghua","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1681\/ASN.2014050489","article-title":"A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome.","volume":"26","author":"Sadowski","year":"2015","journal-title":"J Am Soc Nephrol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1007\/s00467-017-3590-y","article-title":"Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome.","volume":"32","author":"Wang","year":"2017","journal-title":"Pediatr Nephrol."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-57149-5","article-title":"Comprehensive genetic diagnosis of Japanese patients with severe proteinuria.","volume":"10","author":"Nagano","year":"2020","journal-title":"Sci Rep."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0167467","article-title":"Functional validation of an alpha-actinin-4 mutation as a potential cause of an aggressive presentation of adolescent focal segmental glomerulosclerosis: Implications for genetic testing.","volume":"11","author":"Feng","year":"2016","journal-title":"PLoS One."},{"key":"B5","doi-asserted-by":"publisher","first-page":"W350","DOI":"10.1093\/nar\/gky300","article-title":"DynaMut: Predicting the impact of mutations on protein conformation, flexibility and stability.","volume":"46","author":"Rodrigues","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1093\/ndt\/gfp394","article-title":"Functional analysis of promoter mutations in the ACTN4 and SYNPO genes in focal segmental glomerulosclerosis.","volume":"25","author":"Dai","year":"2010","journal-title":"Nephrol Dial Transplant."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3694","DOI":"10.1681\/ASN.2005070706","article-title":"Mutational and biological analysis of alpha-actinin-4 in focal segmental glomerulosclerosis.","volume":"16","author":"Weins","year":"2005","journal-title":"J Am Soc Nephrol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"c87","DOI":"10.1159\/000191198","article-title":"ACTN4 gene mutations and single nucleotide polymorphisms in idiopathic focal segmental glomerulosclerosis.","volume":"111","author":"Dai","year":"2009","journal-title":"Nephron Clin Pract."},{"key":"B9","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1038\/ki.2012.349","article-title":"Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis.","volume":"83","author":"Barua","year":"2013","journal-title":"Kidney Int."},{"key":"B10","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1681\/ASN.2013111155","article-title":"Heterogeneous genetic alterations in sporadic nephrotic syndrome associate with resistance to immunosuppression.","volume":"26","author":"Giglio","year":"2015","journal-title":"J Am Soc Nephrol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1007\/s00467-018-3950-2","article-title":"Genetic diagnosis of steroid-resistant nephrotic syndrome in a longitudinal collection of Czech and Slovak patients: A high proportion of causative variants in NUP93.","volume":"33","author":"Bezd\u00ed\u010dka","year":"2018","journal-title":"Pediatr Nephrol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1093\/hmg\/ddv638","article-title":"Three-layered proteomic characterization of a novel ACTN4 mutation unravels its pathogenic potential in FSGS.","volume":"25","author":"Bartram","year":"2016","journal-title":"Hum Mol Genet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/73456","article-title":"Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.","volume":"24","author":"Kaplan","year":"2000","journal-title":"Nat Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1136\/jmedgenet-2017-104811","article-title":"Clinical genetic testing using a custom-designed steroid-resistant nephrotic syndrome gene panel: Analysis and recommendations.","volume":"54","author":"Sen","year":"2017","journal-title":"J Med Genet."},{"key":"B15","doi-asserted-by":"publisher","first-page":"14","DOI":"10.5414\/CNCS108616","article-title":"Rapid progression to end-stage renal disease in a child with a sporadic ACTN4 mutation.","volume":"3","author":"Kakajiwala","year":"2015","journal-title":"Clin Nephrol Case Stud."},{"key":"B16","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1053\/j.ajkd.2008.01.018","article-title":"Familial focal segmental glomerulosclerosis associated with an ACTN4 mutation and paternal germline mosaicism.","volume":"51","author":"Choi","year":"2008","journal-title":"Am J Kidney Dis."},{"key":"B17","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1016\/j.kint.2016.10.013","article-title":"Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management.","volume":"91","author":"Bierzynska","year":"2017","journal-title":"Kidney Int."},{"key":"B18","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1093\/ndt\/gfy050","article-title":"Panel sequencing distinguishes monogenic forms of nephritis from nephrosis in children.","volume":"34","author":"Schapiro","year":"2019","journal-title":"Nephrol Dial Transplant."},{"key":"B19","doi-asserted-by":"crossref","first-page":"110","DOI":"10.14712\/fb2013059030110","article-title":"Mutational analysis of ACTN4, encoding \u03b1-actinin 4, in patients with focal segmental glomerulosclerosis using HRM method.","volume":"59","author":"Safa\u0159\u00edkov\u00e1","year":"2013","journal-title":"Folia Biol (Praha)."},{"key":"B20","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1074\/mcp.M113.035600","article-title":"Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics.","volume":"13","author":"Fagerberg","year":"2014","journal-title":"Mol Cell Proteomics."},{"key":"B21","doi-asserted-by":"publisher","first-page":"12027","DOI":"10.1074\/jbc.M112.345421","article-title":"Familial focal segmental glomerulosclerosis (FSGS)-linked \u03b1-actinin 4 (ACTN4) protein mutants lose ability to activate transcription by nuclear hormone receptors.","volume":"287","author":"Khurana","year":"2012","journal-title":"J Biol Chem."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1186\/s13578-015-0036-8","article-title":"The role of alpha-actinin-4 in human kidney disease.","volume":"5","author":"Feng","year":"2015","journal-title":"Cell Biosci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"30795","DOI":"10.1074\/jbc.M111.255984","article-title":"Alpha-actinin-4 and CLP36 protein deficiencies contribute to podocyte defects in multiple human glomerulopathies.","volume":"286","author":"Liu","year":"2011","journal-title":"J Biol Chem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1042\/BJ20121824","article-title":"An analysis of splicing, actin-binding properties, heterodimerization and molecular interactions of the non-muscle \u03b1-actinins.","volume":"452","author":"Foley","year":"2013","journal-title":"Biochem J."},{"key":"B25","doi-asserted-by":"publisher","first-page":"22101","DOI":"10.1073\/pnas.1917269117","article-title":"Calcium modulates the domain flexibility and function of an \u03b1-actinin similar to the ancestral \u03b1-actinin.","volume":"117","author":"Pinotsis","year":"2020","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0076360","article-title":"Targeted exome sequencing integrated with clinicopathological information reveals novel and rare mutations in atypical, suspected and unknown cases of Alport syndrome or proteinuria.","volume":"8","author":"Chatterjee","year":"2013","journal-title":"PLoS One."}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2022.930258\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,2]],"date-time":"2024-10-02T15:19:29Z","timestamp":1727882369000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2022.930258\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,25]]},"references-count":26,"alternative-id":["10.3389\/fped.2022.930258"],"URL":"https:\/\/doi.org\/10.3389\/fped.2022.930258","relation":{},"ISSN":["2296-2360"],"issn-type":[{"type":"electronic","value":"2296-2360"}],"subject":[],"published":{"date-parts":[[2022,8,25]]},"article-number":"930258"}}