{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T08:51:50Z","timestamp":1769071910730,"version":"3.49.0"},"reference-count":16,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T00:00:00Z","timestamp":1623628800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T00:00:00Z","timestamp":1623628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med Genomics"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Karyomegalic interstitial nephritis (KIN) is a rare disease entity first described by Burry in 1974. The term KIN was introduced by Mihatsch et al. in 1979. KIN is characterized by chronic tubulointerstitial nephritis associated with enlarged tubular epithelial cell nuclei, which leads to a progressive decline of renal function. The prevalence of this disease is less than 1% of all biopsies, and its pathogenesis is unclear. KIN results from mutations in <jats:italic>FAN1<\/jats:italic> (FANCD2\/FANCI-Associated Nuclease 1), a gene involved in the DNA damage response pathway, particularly in the kidney. In this study, we report two Tunisian consanguineous families with KIN caused by mutations in the <jats:italic>FAN1<\/jats:italic> gene.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Direct sequencing of the coding regions and flanking intronic sequences of the <jats:italic>FAN1<\/jats:italic> gene was performed in three affected members. Three prediction programs (Polyphen-2 software, SIFT, and MutationTaster) were used to predict the functional effect of the detected variations.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Two causative frameshift variants in the <jats:italic>FAN1<\/jats:italic> gene were identified in each family: The previously described frameshift mutation c.2616delA (p.Asp873ThrfsTer17) and a novel mutation c.2603delT (p.Leu868ArgfsTer22) classified as \"pathogenic\" according to the American College of Medical Genetics and Genomics (ACMG) guidelines.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>To our best knowledge, this is the first Tunisian study involving familial cases of KIN with mutations in the <jats:italic>FAN1<\/jats:italic> gene. We hypothesize that these findings can expand the mutational spectrum of KIN and provide valuable information on the genetic cause of KIN.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12920-021-01009-7","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T10:03:03Z","timestamp":1623664983000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["New familial cases of karyomegalic interstitial nephritis with mutations in the FAN1 gene"],"prefix":"10.1186","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2826-1910","authenticated-orcid":false,"given":"Imen","family":"Rejeb","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mouna","family":"Jerbi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Houweyda","family":"Jilani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han\u00e8ne","family":"Gaied","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasmina","family":"Elaribi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Syrine","family":"Hizem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raja","family":"Aoudia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hafedh","family":"Hedri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiraz","family":"Zaied","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salwa","family":"Abid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hassen","family":"Bacha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taieb","family":"BenAbdallah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lamia","family":"BenJemaa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rim","family":"Goucha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,14]]},"reference":[{"issue":"3","key":"1009_CR1","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1002\/path.1711130303","volume":"113","author":"AF Burry","year":"1974","unstructured":"Burry AF. Extreme dysplasia in renal epithelium of a young woman dying from hepatocarcinoma. J Pathol. 1974;113(3):147\u201350.","journal-title":"J Pathol"},{"issue":"2","key":"1009_CR2","first-page":"54","volume":"12","author":"MJ Mihatsch","year":"1979","unstructured":"Mihatsch MJ, Gudat F, Zollinger HU, Heierli C, Th\u00f6len H, Reutter FW. Systemic Karyomegaliy associated with chronic interstitial nephritis. A new disease entity? Clin Nephrol. 1979;12(2):54\u201362.","journal-title":"Clin Nephrol."},{"issue":"20","key":"1009_CR3","doi-asserted-by":"publisher","first-page":"e3349","DOI":"10.1097\/MD.0000000000003349","volume":"95","author":"P Isnard","year":"2016","unstructured":"Isnard P, Rabant M, Labaye J, Antignac C, Knebelmann B, Zaidan M. Karyomegalic interstitial nephritis: a case report and review of the literature. Medicine (Baltimore). 2016;95(20):e3349.","journal-title":"Medicine (Baltimore)."},{"issue":"8","key":"1009_CR4","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1038\/ng.2347","volume":"44","author":"W Zhou","year":"2012","unstructured":"Zhou W, Otto EA, Cluckey A, Airik R, Hurd TW, Chaki M, et al. FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nat Genet. 2012;44(8):910\u20135.","journal-title":"Nat Genet"},{"issue":"4","key":"1009_CR5","doi-asserted-by":"publisher","first-page":"283","DOI":"10.4103\/ijn.IJN_278_19","volume":"30","author":"PJ Koshy","year":"2020","unstructured":"Koshy PJ, Sudhakar DVS, Anupama SH, Mathew M, Parthasarthy R, Thangaraj K, et al. Novel homozygous FAN1 mutation in a familial case of karyomegalic interstitial nephritis. Indian J Nephrol. 2020;30(4):283\u20135. https:\/\/doi.org\/10.4103\/ijn.IJN_278_19.","journal-title":"Indian J Nephrol"},{"issue":"3","key":"1009_CR6","first-page":"201","volume":"3","author":"E Uz","year":"2011","unstructured":"Uz E, Bayram Y, Haltas H, Bavbek N, Kanbay M, Guz G, et al. Karyomegalic tubulointerstitial nephritis: a rare cause of chronic kidney disease. Nephro-Urol Mon Online. 2011;3(3):201\u20133.","journal-title":"Nephro-Urol Mon. Online"},{"issue":"1","key":"1009_CR7","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1186\/s12882-020-01762-4.]","volume":"21","author":"J Dash","year":"2020","unstructured":"Dash J, Saudan P, Paoloni-Giacobino A, Moll S, de Seigneux S. Case report: a 58 -year-old man with small kidneys and elevated liver enzymes. BMC Nephrol. 2020;21(1):107. https:\/\/doi.org\/10.1186\/s12882-020-01762-4.].","journal-title":"BMC Nephrol"},{"key":"1009_CR8","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1002\/dc.20603","volume":"35","author":"D Palmer","year":"1997","unstructured":"Palmer D, Lallu S, Matheson P, Bethwaite P, Tompson K. Karyomegalic interstitial nephritis: a Pitfallin urine cytology. Diagn Cytopathol. 1997;35:179\u201382.","journal-title":"Diagn Cytopathol"},{"issue":"5","key":"1009_CR9","first-page":"291","volume":"149","author":"M Vadiaka","year":"1998","unstructured":"Vadiaka M, Sotsiou F, Koufos C. A case of systemic karyomegaly associated with interstitial nephritis. Ann Med Interne. 1998;149(5):291\u20134.","journal-title":"Ann Med Interne"},{"key":"1009_CR10","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1126\/science.1192656","volume":"329","author":"T Liu","year":"2010","unstructured":"Liu T, Ghosal G, Yuan J. FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair. Science. 2010;329:693\u20136.","journal-title":"Science"},{"key":"1009_CR11","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.cell.2010.06.022","volume":"142","author":"K Kratz","year":"2010","unstructured":"Kratz K, Sch\u00f6pf B, Kaden S, Sendoel A, Eberhard R, Lademann C, et al. Deficiency of FANCD2-associated nuclease KIAA1018.FAN1 sensitizes cells to interstrand crosslinking agents. Cell. 2010;142:77\u201388.","journal-title":"Cell"},{"key":"1009_CR12","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.cell.2010.06.021","volume":"142","author":"C MacKay","year":"2010","unstructured":"MacKay C, D\u00e9clais AC, Lundin C, Agostinho A, Deans AJ, MacArtney TJ, et al. Identification of KIAA1018.FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2. Cell. 2010;142:65\u201376.","journal-title":"Cell"},{"key":"1009_CR13","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.molcel.2010.06.023","volume":"39","author":"A Smogorzewska","year":"2010","unstructured":"Smogorzewska A, Desetty R, Saito TT, Schlabach M, Lach FP, Sowa ME, et al. A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. Mol Cell. 2010;39:36\u201347.","journal-title":"Mol Cell"},{"issue":"6","key":"1009_CR14","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1101\/gad.276287.115","volume":"30","author":"C Lachaud","year":"2016","unstructured":"Lachaud C, Slean M, Marchesi F, Lock C, Odell E, Castor D, et al. Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice. Genes Dev. 2016;30(6):639\u201344.","journal-title":"Genes Dev"},{"issue":"3","key":"1009_CR15","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/j.cell.2012.06.028","volume":"150","author":"M Chaki","year":"2012","unstructured":"Chaki M, Airik R, Ghosh AK, Giles RH, Chen R, Slaats GG, Wang H, et al. Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell. 2012;150(3):533\u201348.","journal-title":"Cell"},{"issue":"1","key":"1009_CR16","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1186\/s12882-020-01733-9","volume":"21","author":"S Law","year":"2020","unstructured":"Law S, Gillmore J, Gilbertson JA, Bass P, Salama AD. Karyomegalic interstitial nephritis with a novel FAN1 gene mutation and concurrent ALECT2 amyloidosis. BMC Nephrol. 2020;21(1):74. https:\/\/doi.org\/10.1186\/s12882-020-01733-9.","journal-title":"BMC Nephrol"}],"container-title":["BMC Medical Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-021-01009-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12920-021-01009-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-021-01009-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T10:04:49Z","timestamp":1623665089000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmedgenomics.biomedcentral.com\/articles\/10.1186\/s12920-021-01009-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,14]]},"references-count":16,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1009"],"URL":"https:\/\/doi.org\/10.1186\/s12920-021-01009-7","relation":{},"ISSN":["1755-8794"],"issn-type":[{"value":"1755-8794","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,14]]},"assertion":[{"value":"1 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All procedures performed in the present study were approved by The Ethical Review Committee of Mongi Slim Hospital (La Marsa, Tunisia) and were also in accordance with the Declaration of Helsinki. Written informed consent was obtained from all individuals.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written consent has been obtained from all participants included in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"160"}}