{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T01:53:44Z","timestamp":1784944424045,"version":"3.55.0"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T00:00:00Z","timestamp":1723420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Grants-in-Aid for Scientific Research","doi-asserted-by":"crossref","award":["23K07698"],"award-info":[{"award-number":["23K07698"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Male patients with X-linked Alport syndrome (XLAS) generally develop end-stage kidney disease in early or middle adulthood and show distinct genotype\u2013phenotype correlations. However, female patients show various phenotypes ranging from asymptomatic to severe with no genotype\u2013phenotype correlations. The factors affecting the severity of XLAS in female patients are unclear. Since X-chromosome inactivation (XCI) affects the severity of certain female X-linked diseases, we investigated whether genotype and XCI were associated with XLAS severity in female patients in a large Japanese cohort.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Among 139 female patients with genetically diagnosed XLAS at our institution, we conducted XCI analysis on peripheral blood leucocytes using the human androgen receptor assay method and analysed two cohorts. In 74 adult female patients we evaluated the correlation between kidney function [creatinine estimated glomerular filtration rate (Cr-eGFR) optimized for Japanese individuals] and genotype\/XCI using multivariable linear regression analysis and in 65 paediatric female patients we evaluated the correlation between kidney function (Cr-eGFR optimized for Japanese individuals) and genotype\/XCI using multivariable linear regression analysis. We also investigated the correlation between the development of proteinuria (urine protein:creatinine ratio above normal for the patient's age) and genotype\/XCI using multivariable Cox proportional hazards analysis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In adult female patients, the XCI pattern was significantly associated with Cr-eGFR (regression coefficient estimate \u22120.53, P\u00a0=\u00a0.004), whereas genotype was not (P\u00a0=\u00a0.892). In paediatric female patients, both genotype and XCI pattern were significant independent risk factors for the development of proteinuria {hazard ratio [HR] 3.702 [95% confidence interval (CI) 1.681\u20138.150], P\u00a0=\u00a0.001 and HR 1.043 [95% CI 1.061\u20131.070], P\u00a0=\u00a0.001, respectively}, whereas both genotype and XCI pattern were not associated with Cr-eGFR (P\u00a0=\u00a0.20 and P\u00a0=\u00a0.67, respectively).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Genotype and XCI are factors associated with severity in females with XLAS.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ndt\/gfae182","type":"journal-article","created":{"date-parts":[[2024,8,11]],"date-time":"2024-08-11T13:41:13Z","timestamp":1723383673000},"page":"688-695","source":"Crossref","is-referenced-by-count":8,"title":["Genotype and X-chromosome inactivation are associated with disease severity in females with X-linked Alport syndrome"],"prefix":"10.1093","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3021-8348","authenticated-orcid":false,"given":"Ryota","family":"Suzuki","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Kobe ,","place":["Japan"]},{"name":"Department of Pediatrics, Hokkaido University Graduate School of Medicine , Sapporo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8387-8008","authenticated-orcid":false,"given":"Nana","family":"Sakakibara","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Kobe ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sae","family":"Murakami","sequence":"additional","affiliation":[{"name":"Clinical and Translational Research Center, Kobe University Hospital , Kobe, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Ichikawa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Kobe ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Kitakado","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Kobe ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chika","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Kobe ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Kobe ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eri","family":"Okada","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Kobe ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Kondo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Kobe ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuya","family":"Aoto","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Kobe ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Ishiko","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Kobe ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Ishimori","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Kobe ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4946-1345","authenticated-orcid":false,"given":"China","family":"Nagano","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Kobe ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiko","family":"Yamamura","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Kobe ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1655-6030","authenticated-orcid":false,"given":"Tomoko","family":"Horinouchi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Kobe ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6029-451X","authenticated-orcid":false,"given":"Takayuki","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hokkaido University Graduate School of Medicine , Sapporo , and","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0290-3137","authenticated-orcid":false,"given":"Kandai","family":"Nozu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Kobe ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,8,12]]},"reference":[{"key":"2025040116475961100_bib1","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1681\/ASN.V114649","article-title":"X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males","volume":"11","author":"Jais","year":"2000","journal-title":"J Am Soc Nephrol"},{"key":"2025040116475961100_bib2","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1681\/ASN.2009070784","article-title":"Genotype-phenotype correlation in X-linked Alport syndrome","volume":"21","author":"Bekheirnia","year":"2010","journal-title":"J Am Soc Nephrol"},{"key":"2025040116475961100_bib3","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1016\/j.kint.2020.06.038","article-title":"Genotype-phenotype correlations influence the response to angiotensin-targeting drugs in Japanese patients with male X-linked Alport syndrome","volume":"98","author":"Yamamura","year":"2020","journal-title":"Kidney Int"},{"key":"2025040116475961100_bib4","doi-asserted-by":"publisher","first-page":"2603","DOI":"10.1097\/01.ASN.0000090034.71205.74","article-title":"X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a \u201cEuropean Community Alport Syndrome Concerted Action\u201d study","volume":"14","author":"Jais","year":"2003","journal-title":"J Am Soc Nephrol"},{"key":"2025040116475961100_bib5","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1016\/j.ekir.2017.04.011","article-title":"Natural history and genotype-phenotype correlation in female X-linked Alport syndrome","volume":"2","author":"Yamamura","year":"2017","journal-title":"Kidney Int Rep"},{"key":"2025040116475961100_bib6","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1186\/1750-1172-7-82","article-title":"Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy","volume":"7","author":"Juan-Mateu","year":"2012","journal-title":"Orphanet J Rare Dis"},{"key":"2025040116475961100_bib7","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1111\/hae.14186","article-title":"Genetic causes of haemophilia in women and girls","volume":"27","author":"Miller","year":"2021","journal-title":"Haemophilia"},{"key":"2025040116475961100_bib8","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1007\/s10157-020-01926-4","article-title":"Onset mechanism of a female patient with Dent disease 2","volume":"24","author":"Okamoto","year":"2020","journal-title":"Clin Exp Nephrol"},{"key":"2025040116475961100_bib9","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1038\/190372a0","article-title":"Gene action in the X-chromosome of the mouse (Mus musculus L.)","volume":"190","author":"Lyon","year":"1961","journal-title":"Nature"},{"key":"2025040116475961100_bib10","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1086\/507565","article-title":"X chromosome-inactivation patterns of 1,005 phenotypically unaffected females","volume":"79","author":"Amos-Landgraf","year":"2006","journal-title":"Am J Hum Genet"},{"key":"2025040116475961100_bib11","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1182\/blood.V88.1.59.59","article-title":"Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age","volume":"88","author":"Busque","year":"1996","journal-title":"Blood"},{"key":"2025040116475961100_bib12","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1093\/ndt\/gfp551","article-title":"X-inactivation modifies disease severity in female carriers of murine X-linked Alport syndrome","volume":"25","author":"Rheault","year":"2010","journal-title":"Nephrol Dial Transplant"},{"key":"2025040116475961100_bib13","doi-asserted-by":"publisher","first-page":"953643","DOI":"10.3389\/fmed.2022.953643","article-title":"Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age","volume":"9","author":"Gunthner","year":"2022","journal-title":"Front Med (Lausanne)"},{"key":"2025040116475961100_bib14","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s00467-011-1836-7","article-title":"Women and Alport syndrome","volume":"27","author":"Rheault","year":"2012","journal-title":"Pediatr Nephrol"},{"key":"2025040116475961100_bib15","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.2215\/CJN.00580116","article-title":"Alport syndrome in women and girls","volume":"11","author":"Savige","year":"2016","journal-title":"Clin J Am Soc Nephrol"},{"key":"2025040116475961100_bib16","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1136\/jmg.29.9.663","article-title":"X inactivation patterns in females with Alport's syndrome: a means of selecting against a deleterious gene?","volume":"29","author":"Vetrie","year":"1992","journal-title":"J Med Genet"},{"key":"2025040116475961100_bib17","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.2215\/CJN.03120322","article-title":"Digenic Alport syndrome","volume":"17","author":"Savige","year":"2022","journal-title":"Clin J Am Soc Nephrol"},{"key":"2025040116475961100_bib18","doi-asserted-by":"publisher","first-page":"2244","DOI":"10.1681\/ASN.2018030228","article-title":"Detection of splicing abnormalities and genotype-phenotype correlation in X-linked Alport syndrome","volume":"29","author":"Horinouchi","year":"2018","journal-title":"J Am Soc Nephrol"},{"key":"2025040116475961100_bib19","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.ekir.2021.10.012","article-title":"Last nucleotide substitutions of COL4A5 exons cause aberrant splicing","volume":"7","author":"Aoto","year":"2022","journal-title":"Kidney Int Rep"},{"key":"2025040116475961100_bib20","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1007\/s10157-022-02294-x","article-title":"Aberrant splicing caused by exonic single nucleotide variants positioned 2nd or 3rd to the last nucleotide in the COL4A5 gene","volume":"27","author":"Okada","year":"2023","journal-title":"Clin Exp Nephrol"},{"key":"2025040116475961100_bib21","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1038\/s41431-021-00858-1","article-title":"Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria","volume":"29","author":"Savige","year":"2021","journal-title":"Eur J Hum Genet"},{"key":"2025040116475961100_bib22","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1053\/j.ajkd.2008.12.034","article-title":"Revised equations for estimated GFR from serum creatinine in Japan","volume":"53","author":"Matsuo","year":"2009","journal-title":"Am J Kidney Dis"},{"key":"2025040116475961100_bib23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10157-018-1648-1","article-title":"Essential points from evidence-based clinical practice guidelines for chronic kidney disease 2018","volume":"23","author":"Japanese Society of Nephrology","year":"2019","journal-title":"Clin Exp Nephrol"},{"key":"2025040116475961100_bib24","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1007\/s10157-024-02497-4","article-title":"Essential points from evidence-based clinical practice guideline for chronic kidney disease 2023","volume":"28","author":"Japanese Society of Nephrology","year":"2024","journal-title":"Clin Exp Nephrol"},{"key":"2025040116475961100_bib25","doi-asserted-by":"publisher","first-page":"1737","DOI":"10.1056\/NEJMoa2102953","article-title":"New creatinine- and cystatin C-based equations to estimate GFR without race","volume":"385","author":"Inker","year":"2021","journal-title":"N Engl J Med"},{"key":"2025040116475961100_bib26","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1007\/s10157-013-0856-y","article-title":"Creatinine-based equation to estimate the glomerular filtration rate in Japanese children and adolescents with chronic kidney disease","volume":"18","author":"Uemura","year":"2014","journal-title":"Clin Exp Nephrol"},{"key":"2025040116475961100_bib27","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1007\/s10157-017-1460-3","article-title":"Creatinine-based estimated glomerular filtration rate for children younger than 2 years","volume":"22","author":"Uemura","year":"2018","journal-title":"Clin Exp Nephrol"},{"key":"2025040116475961100_bib28","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1681\/ASN.2008030287","article-title":"New equations to estimate GFR in children with CKD","volume":"20","author":"Schwartz","year":"2009","journal-title":"J Am Soc Nephrol"},{"key":"2025040116475961100_bib29","first-page":"1229","article-title":"Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation","volume":"51","author":"Allen","year":"1992","journal-title":"Am J Hum Genet"},{"key":"2025040116475961100_bib30","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/bmt.2012.244","article-title":"Investigation of the freely available easy-to-use software \u2018EZR\u2019 for medical statistics","volume":"48","author":"Kanda","year":"2013","journal-title":"Bone Marrow Transplant"},{"key":"2025040116475961100_bib31","doi-asserted-by":"publisher","first-page":"2454","DOI":"10.1016\/j.ekir.2022.08.021","article-title":"A systematic review of pathogenic COL4A5 variants and proteinuria in women and girls with X-linked Alport syndrome","volume":"7","author":"Gibson","year":"2022","journal-title":"Kidney Int Rep"},{"key":"2025040116475961100_bib32","doi-asserted-by":"publisher","first-page":"1981","DOI":"10.1007\/s00467-022-05430-7","article-title":"Approach to genetic testing to optimize the safety of living donor transplantation in Alport syndrome spectrum","volume":"37","author":"Caliskan","year":"2022","journal-title":"Pediatr Nephrol"},{"key":"2025040116475961100_bib33","doi-asserted-by":"publisher","first-page":"1961","DOI":"10.1681\/ASN.2020060777","article-title":"Uncovering modifier genes of X-linked Alport syndrome using a novel multiparent mouse model","volume":"32","author":"Takemon","year":"2021","journal-title":"J Am Soc Nephrol"},{"key":"2025040116475961100_bib34","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1038\/s41431-018-0291-3","article-title":"Skewed X-inactivation is common in the general female population","volume":"27","author":"Shvetsova","year":"2019","journal-title":"Eur J Hum Genet"},{"key":"2025040116475961100_bib35","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1007\/s10577-023-09717-9","article-title":"X-chromosome inactivation patterns depend on age and tissue but not conception method in humans","volume":"31","author":"Juchniewicz","year":"2023","journal-title":"Chromosome Res"},{"key":"2025040116475961100_bib36","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1007\/BF02185765","article-title":"X-chromosome methylation ratios as indicators of chromosomal activity: evidence of intraindividual divergencies among tissues of different embryonal origin","volume":"97","author":"Azofeifa","year":"1996","journal-title":"Hum Genet"},{"key":"2025040116475961100_bib37","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1038\/s10038-018-0415-1","article-title":"Development of ultra-deep targeted RNA sequencing for analyzing X-chromosome inactivation in female Dent disease","volume":"63","author":"Minamikawa","year":"2018","journal-title":"J Hum Genet"},{"key":"2025040116475961100_bib38","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1007\/s10157-016-1352-y","article-title":"Female X-linked Alport syndrome with somatic mosaicism","volume":"21","author":"Yokota","year":"2017","journal-title":"Clin Exp Nephrol"},{"key":"2025040116475961100_bib39","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1007\/s004390000382","article-title":"Age- and tissue-specific variation of X chromosome inactivation ratios in normal women","volume":"107","author":"Sharp","year":"2000","journal-title":"Hum Genet"}],"container-title":["Nephrology Dialysis Transplantation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ndt\/advance-article-pdf\/doi\/10.1093\/ndt\/gfae182\/58938663\/gfae182.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ndt\/article-pdf\/40\/4\/688\/58938663\/gfae182.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ndt\/article-pdf\/40\/4\/688\/58938663\/gfae182.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T17:51:38Z","timestamp":1743529898000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ndt\/article\/40\/4\/688\/7732058"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,12]]},"references-count":39,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,8,12]]},"published-print":{"date-parts":[[2025,4,1]]}},"URL":"https:\/\/doi.org\/10.1093\/ndt\/gfae182","relation":{},"ISSN":["0931-0509","1460-2385"],"issn-type":[{"value":"0931-0509","type":"print"},{"value":"1460-2385","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,4]]},"published":{"date-parts":[[2024,8,12]]}}}