{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T18:28:07Z","timestamp":1790447287864,"version":"4.1.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,2,28]],"date-time":"2020-02-28T00:00:00Z","timestamp":1582848000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,2,28]],"date-time":"2020-02-28T00:00:00Z","timestamp":1582848000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81660117"],"award-info":[{"award-number":["81660117"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81160087"],"award-info":[{"award-number":["81160087"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Fund of Inner Mongolia Autonomous Region","award":["2018MS08008"],"award-info":[{"award-number":["2018MS08008"]}]},{"name":"2015 Science and Technology Planning Project of Inner Mongolia Autonomous Region","award":["201502107"],"award-info":[{"award-number":["201502107"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Nephrol"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Background<\/jats:title>\n<jats:p>Familial renal glucosuria (FRG) is characterized by persistent glucosuria without other impairments of tubular function in the presence of normal serum glucose. SGLT2, which is almost exclusively expressed in the kidney, accounts for most of the glucose reabsorption. Recently, some studies have confirmed that <jats:italic>SLC5A2<\/jats:italic> mutations are responsible for the pathogenesis of familial renal glucosuria, but FRG cases are still rare. Furthermore, there are a few reports about splice-site mutations in previous studies, but the effect of these variants at the mRNA level has hardly been verified.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>Ten patients were recruited in our renal division because of persistent glucosuria, and clinical data of the patients and their family members were recorded as much as possible. The entire coding region and adjacent intronic segments of <jats:italic>SLC5A2<\/jats:italic> were sequenced in FRG patients and their relatives. Permanent growing lymphoblastoid cell lines from FRG patients were established to better preserve genetic information.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>A total of nine different mutations were identified: IVS1-16C\u2009&gt;\u2009A, c.305C\u2009&gt;\u2009T\/p.(A102V), c.395G\u2009&gt;\u2009A\/p.(R132H), c.736C\u2009&gt;\u2009T\/p.(P246S), c.886(\u221210_-31)delGCAAGCGGGCAGCTGAACGCCC, c.1152_1163delGGTCATGCTGGC\/p.(Val385_Ala388del), c.1222G\u2009&gt;\u2009T\/p.(D408Y), c.1496G\u2009&gt;\u2009A\/p.(R499H) and c.1540C\u2009&gt;\u2009T\/p.(P514S); two novel mutations in <jats:italic>SLC5A2<\/jats:italic>, c.1222G\u2009&gt;\u2009T\/p.(D408Y) and c.1496G\u2009&gt;\u2009A\/p.(R499H), were identified in the Chinese FRG pedigrees. Ten individuals with heterozygous or compound heterozygous variants had glucosuria in the range of 3.1 to 37.6\u2009g\/d.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>We screened ten additional Chinese FRG pedigrees for mutations in the <jats:italic>SLC5A2<\/jats:italic> gene and found nine mutations, including two novel mutations. Most variants were private, but IVS1-16C\u2009&gt;\u2009A and c.886(\u221210_-31) del may be high frequency splice-site mutations that could be preferentially screened when variants cannot be found in the <jats:italic>SLC5A2<\/jats:italic> exon. Furthermore, we successfully established a permanent growing lymphoblastoid cell line from patients with FRG, which could facilitate further studies of the <jats:italic>SLC5A2<\/jats:italic> gene. The current study provides a valuable clue for further research on the molecular mechanism of SGLT2.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s12882-020-01725-9","type":"journal-article","created":{"date-parts":[[2020,2,28]],"date-time":"2020-02-28T11:03:24Z","timestamp":1582887804000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["SLC5A2 mutations, including two novel mutations, responsible for renal glucosuria in Chinese families"],"prefix":"10.1186","volume":"21","author":[{"given":"Lei","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,28]]},"reference":[{"key":"1725_CR1","doi-asserted-by":"publisher","first-page":"F10","DOI":"10.1152\/ajprenal.2001.280.1.F10","volume":"280","author":"EM Wright","year":"2001","unstructured":"Wright EM. Renal Na(+)-glucose cotransporters. Am J Physiol Renal Physiol. 2001;280:F10\u20138.","journal-title":"Am J Physiol Renal Physiol"},{"key":"1725_CR2","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1172\/JCI116972","volume":"93","author":"Y Kanai","year":"1994","unstructured":"Kanai Y, Lee WS, You G, Brown D, Hediger MA. The human kidney low affinity Na(+)\/glucose cotransporter SGLT2: delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest. 1994;93:397\u2013404.","journal-title":"J Clin Invest"},{"key":"1725_CR3","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1006\/geno.1993.1411","volume":"17","author":"RG Wells","year":"1993","unstructured":"Wells RG, Mohandas TK, Hediger MA. Localization of the Na+\/glucose cotransporter gene SGLT2 to human chromosome 16 close to the centromere. Genomics. 1993;17:787\u20139.","journal-title":"Genomics"},{"key":"1725_CR4","doi-asserted-by":"publisher","first-page":"3874","DOI":"10.1093\/ndt\/gfn386","volume":"23","author":"J Calado","year":"2008","unstructured":"Calado J, Sznajer Y, Metzger D, Rita A, Hogan MC, Kattamis A, et al. Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion. Nephrol Dial Transplant. 2008;23:3874\u20139.","journal-title":"Nephrol Dial Transplant"},{"key":"1725_CR5","doi-asserted-by":"publisher","first-page":"2873","DOI":"10.1097\/01.ASN.0000092790.89332.D2","volume":"14","author":"R Santer","year":"2003","unstructured":"Santer R, Kinner M, Lassen CL, Schneppenheim R, Eggert P, Bald M, et al. Analysis of the SGLT2 gene in patients with renal Glucosuria. J Am Soc Nephrol. 2003;14:2873\u201382.","journal-title":"J Am Soc Nephrol"},{"key":"1725_CR6","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1038\/sj.ki.5000194","volume":"69","author":"J Calado","year":"2006","unstructured":"Calado J, Loeffler J, Sakallioglu O, Gok F, Lhotta K, Barata J, et al. Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting. Kidney Int. 2006;69:852\u20135.","journal-title":"Kidney Int"},{"key":"1725_CR7","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1007\/s00439-002-0820-5","volume":"111","author":"LP Van den Heuvel","year":"2002","unstructured":"Van den Heuvel LP, Assink K, Willemsen M, Monnens L. Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2). Hum Genet. 2002;111:544\u20137.","journal-title":"Hum Genet"},{"key":"1725_CR8","doi-asserted-by":"publisher","first-page":"2893","DOI":"10.1093\/ndt\/gfh426","volume":"19","author":"J Francis","year":"2004","unstructured":"Francis J, Zhang J, Farhi A, Carey H, Geller DS. A novel SGLT2 mutation in a patient with autosomal recessive renal glucosuria. Nephrol Dial Transplant. 2004;19:2893\u20135.","journal-title":"Nephrol Dial Transplant"},{"key":"1725_CR9","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1007\/s00439-003-1054-x","volume":"114","author":"J Calado","year":"2004","unstructured":"Calado J, Soto K, Clemente C, Correia P, Rueff J. Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria. Hum Genet. 2004;114:314\u20136.","journal-title":"Hum Genet"},{"key":"1725_CR10","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.ymgme.2004.01.018","volume":"82","author":"R Kleta","year":"2004","unstructured":"Kleta R, Stuart C, Gill FA, Gahl WA. Renal glucosuria due to SGLT2 mutations. Mol Genet Metab. 2004;82:56\u20138.","journal-title":"Mol Genet Metab"},{"key":"1725_CR11","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1111\/j.1523-1755.2005.00053.x","volume":"67","author":"D Magen","year":"2005","unstructured":"Magen D, Sprecher E, Zelikovic I, Skorecki K. A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessive renal glucosuria and aminoaciduria. Kidney Int. 2005;67:34\u201341.","journal-title":"Kidney Int"},{"key":"1725_CR12","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1002\/humu.22714","volume":"36","author":"L Yu","year":"2015","unstructured":"Yu L, Hou P, Lv JC, Liu GP, Zhang H. Novel SLC5A2 variants contribute to renal Glucosuria in Chinese families: abnormal expression and dysfunction of variant SLC5A2. Hum Mutat. 2015;36:79\u201386.","journal-title":"Hum Mutat"},{"key":"1725_CR13","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1007\/s00439-010-0927-z","volume":"129","author":"L Yu","year":"2011","unstructured":"Yu L, Lv J-C, Zhou X-j, Zhu L, Hou P, Zhang H. Abnormal expression and dysfunction of novel SGLT2 mutations identified in familial renal glucosuria patients. Hum Genet. 2011;129:335\u201344.","journal-title":"Hum Genet"},{"key":"1725_CR14","doi-asserted-by":"publisher","first-page":"2237","DOI":"10.1007\/s11255-014-0755-5","volume":"46","author":"L Yu","year":"2014","unstructured":"Yu L, Hou P, Lv JC, Liu GP, Zhang H. A novel sodium-glucose co-transporter 2 gene (SGLT2) mutation contributes to the abnormal expression of SGLT2 in renal tissues in familial renal glucosuria. Int Urol Nephrol. 2014;46:2237\u20138.","journal-title":"Int Urol Nephrol"},{"key":"1725_CR15","doi-asserted-by":"publisher","first-page":"649","DOI":"10.3892\/etm.2016.3388","volume":"12","author":"L Yu","year":"2016","unstructured":"Yu L, Hou P, Liu GP, Zhang H. A novel SLC5A2 mutation contributes to familial renal glucosuria: abnormal expression in renal tissues. Experimental and Therapeutic Medicine. 2016;12:649\u201352.","journal-title":"Experimental and Therapeutic Medicine"},{"key":"1725_CR16","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s12882-016-0244-4","volume":"17","author":"L Yu","year":"2016","unstructured":"Yu L, Xu Q, Ping H, Hong Z. Decreased expression and function of sodium-glucose co-transporter 2 from a novel C-terminal mutation: a case report. BMC Nephrol. 2016;17:31.","journal-title":"BMC Nephrol"},{"key":"1725_CR17","doi-asserted-by":"publisher","first-page":"2394","DOI":"10.1093\/ndt\/gfh366","volume":"19","author":"S Scholl-Burgi","year":"2004","unstructured":"Scholl-Burgi S, Santer R, Ehrich JH. Long-term outcome of renal glucosuria type 0: the original patient and his natural history. Nephrol Dial Transplant. 2004;19:2394\u20136.","journal-title":"Nephrol Dial Transplant"},{"key":"1725_CR18","first-page":"285","volume":"8","author":"M Isaji","year":"2007","unstructured":"Isaji M. Sodium-glucose cotransporter inhibitors for diabetes. Curr Opin Investig Drugs. 2007;8:285\u201392.","journal-title":"Curr Opin Investig Drugs"},{"key":"1725_CR19","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1093\/nar\/16.3.1215","volume":"16","author":"SA Miller","year":"1988","unstructured":"Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.","journal-title":"Nucleic Acids Res"},{"key":"1725_CR20","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1007\/BF00279094","volume":"73","author":"N Heidemarie","year":"1986","unstructured":"Heidemarie N. A routine method for the establishment of permanent growing lymphoblastoid cell lines. Hum Genet. 1986;73:320\u20136.","journal-title":"Hum Genet"},{"key":"1725_CR21","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nmeth0410-248","volume":"7","author":"IA Adzhubei","year":"2010","unstructured":"Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248\u20139.","journal-title":"Nat Methods"},{"key":"1725_CR22","doi-asserted-by":"publisher","first-page":"33920","DOI":"10.1038\/srep33920","volume":"6","author":"X Zhao","year":"2016","unstructured":"Zhao X, Cui L, Lang Y, Liu T, Lu J, Wang C, et al. A recurrent deletion in the SLC5A2 gene including the intron 7 branch site responsible for familial renal glucosuria. Sci Rep. 2016;6:33920.","journal-title":"Sci Rep"},{"key":"1725_CR23","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.cca.2018.12.024","volume":"490","author":"S Wang","year":"2019","unstructured":"Wang S, Zhao X, Zhang R, Wang C, Han Y, Shao L. Identification of ten novel SLC5A2 mutations and determination of the renal threshold for glucose excretion in Chinese patients with familial renal glucosuria. Clin Chim Acta. 2019;490:102\u20136.","journal-title":"Clin Chim Acta"},{"key":"1725_CR24","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1111\/j.1365-2796.2006.01746.x","volume":"261","author":"EM Wright","year":"2007","unstructured":"Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. 2007;261:44\u201352.","journal-title":"J Intern Med"},{"key":"1725_CR25","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1007\/s00424-003-1202-0","volume":"447","author":"EM Wright","year":"2004","unstructured":"Wright EM, Turk E. The sodium\/glucose cotransport family SLC5. Pflugers Arch. 2004;447:510\u20138.","journal-title":"Pflugers Arch"},{"key":"1725_CR26","first-page":"178","volume":"23","author":"R Santer","year":"2000","unstructured":"Santer R, Kinner M, Schneppenheim R. The molecular basis of renal glucosuria: mutations in the gene for a renal glucose transporter (SGLT2). J Inherit Metab Dis. 2000;23:178.","journal-title":"J Inherit Metab Dis"},{"key":"1725_CR27","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1007\/s00467-012-2109-9","volume":"27","author":"H Lee","year":"2012","unstructured":"Lee H, Han KH, Park HW, Shin JI, Kim CJ, Namgung MK, et al. Familial renal glucosuria: a clinicogenetic study of 23 additional cases. Pediatr Nephrol. 2012;27:1091\u20135.","journal-title":"Pediatr Nephrol"},{"key":"1725_CR28","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1002\/gcc.2870080108","volume":"8","author":"VS Lestou","year":"1993","unstructured":"Lestou VS, De Braekeleer M, Strehl S, Ott G, Gadner H, Ambros PF. Non-random integration of Epstein-Barr virus in lymphoblastoid cell lines. Genes Chromosomes Cancer. 1993;8:38\u201348.","journal-title":"Genes Chromosomes Cancer"},{"key":"1725_CR29","first-page":"911","volume":"95","author":"KD Wuu","year":"1996","unstructured":"Wuu KD, Chen YJ, Wuu SW. Frequency and distribution of chromosomal integration sites of the Epstein-Barr virus genome. J Formos Med Assoc. 1996;95:911\u20136.","journal-title":"J Formos Med Assoc"},{"key":"1725_CR30","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.jviromet.2006.05.013","volume":"136","author":"J Gao","year":"2000","unstructured":"Gao J, Luo X, Tang K, Li X, Li G. Epstein-Barr virus integrates frequently into chromosome 4q, 2q, 1q and 7q of Burkitt's lymphoma cell line (Raji). J Virol Methods. 2000;136:193\u20139.","journal-title":"J Virol Methods"}],"container-title":["BMC Nephrology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12882-020-01725-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12882-020-01725-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12882-020-01725-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,27]],"date-time":"2021-02-27T00:34:34Z","timestamp":1614386074000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcnephrol.biomedcentral.com\/articles\/10.1186\/s12882-020-01725-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,28]]},"references-count":30,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["1725"],"URL":"https:\/\/doi.org\/10.1186\/s12882-020-01725-9","relation":{},"ISSN":["1471-2369"],"issn-type":[{"value":"1471-2369","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,28]]},"assertion":[{"value":"16 July 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 February 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 February 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The study protocol was approved by the Medical Ethics Committee of Inner Mongolia People\u2019s Hospital (Hohhot, China). Written informed consent was obtained from all participants prior to participating in the study.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent for publication was obtained from the participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"69"}}