{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T13:11:27Z","timestamp":1783948287597,"version":"3.55.0"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"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. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Mutations in the\n                      <jats:italic>HNF1B<\/jats:italic>\n                      gene can cause developmental and functional abnormalities in multiple organs such as the pancreas, kidneys, and liver. The patient is a 19-year-old male with normal growth and development, presenting with a 9-year history of diabetes that remains poorly controlled despite intensive subcutaneous insulin therapy. His clinical features include surgically managed bilateral cataracts, hyperuricemia, and bilateral renal cysts. Family history is significant for diabetes in paternal and maternal uncles.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This combination of early onset, multiorgan involvement, and familial pattern strongly suggests monogenic diabetes, indicating the need for genetic analysis to confirm the diagnosis and guide management. This study performed genetic sequencing on a patient suspected of maturity-onset diabetes of the young (MODY), followed by a Minigene assay on the identified variant of uncertain significance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Trio-whole-genome sequencing (Trio-WGS) identified the\n                      <jats:italic>de novo HNF1B<\/jats:italic>\n                      splice-site variant (NM_000458.4: c.544+3_544+6delAAGT). The Minigene experiments indicate that this point mutation affects the splicing function of\n                      <jats:italic>HNF1B<\/jats:italic>\n                      gene with producing a truncated protein of 170 amino acids.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      In this study, we identified a\n                      <jats:italic>de novo<\/jats:italic>\n                      splicing mutation in the\n                      <jats:italic>HNF1B<\/jats:italic>\n                      gene through combined genomic analysis and functional verification, confirming that it leads to aberrant mRNA splicing. For patients with early-onset diabetes and extra-renal manifestations, if genetic screening for\n                      <jats:italic>HNF1B<\/jats:italic>\n                      exons and canonical splice sites yields negative results, the pathogenic potential of variants in introns and non-canonical splice sites should be carefully considered.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1777094","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T04:27:22Z","timestamp":1775795242000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Functional validation of a non-canonical HNF1B splice-site variant in MODY5"],"prefix":"10.3389","volume":"17","author":[{"given":"Xinran","family":"Gong","sequence":"first","affiliation":[{"name":"Henan Key Laboratory of Rare Diseases, Department of Endocrinology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology","place":["Luoyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Anyang Steel General Hospital","place":["Anyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaobo","family":"Ma","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Rare Diseases, Department of Endocrinology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology","place":["Luoyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Rare Diseases, Department of Endocrinology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology","place":["Luoyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyan","family":"Hu","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Rare Diseases, Department of Endocrinology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology","place":["Luoyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Rare Diseases, Department of Endocrinology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology","place":["Luoyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huifang","family":"Peng","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Rare Diseases, Department of Endocrinology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology","place":["Luoyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2020.107640","article-title":"Clinical features complications and treatment of rarer forms of maturity-onset diabetes of the young (MODY) - A review","volume":"35","author":"Aarthy","year":"2021","journal-title":"J Diabetes Complications"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/dme.2_13570","article-title":"Redefining the pathogenicity of Maturity Onset Diabetes of the Young (MODY) genes: BLK, PAX4 and KLF11 do not cause MODY","author":"Laver","year":"","journal-title":"Diabetic Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/07435800.2024.2388606","article-title":"Monogenic diabetes: A comprehensive overview and therapeutic management of subtypes of mody","volume":"50","author":"Sharma","year":"2025","journal-title":"Endocr Res"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.06810909","article-title":"Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases","volume":"5","author":"Heidet","year":"2010","journal-title":"Clin J Am Soc Nephrol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2018.10.031","article-title":"Monogenic causes of chronic kidney disease in adults","volume":"95","author":"Connaughton","year":"2019","journal-title":"Kidney Int"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-2189","article-title":"Expanded clinical spectrum in hepatocyte nuclear factor 1b-maturity-onset diabetes of the young","volume":"94","author":"Raile","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"B7","doi-asserted-by":"publisher","first-page":"15","DOI":"10.5603\/EP.2015.0004","article-title":"Atypical phenotypic features among carriers of a novel Q248X nonsense mutation in the HNF1B gene","volume":"66","author":"Hogendorf","year":"2015","journal-title":"Endokrynol Pol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1038\/s41572-023-00421-w","article-title":"Monogenic diabetes","volume":"9","author":"Bonnefond","year":"2023","journal-title":"Nat Rev Dis Primers"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2020.09.042","article-title":"Variable expressivity of HNF1B nephropathy from renal cysts and diabetes to medullary sponge kidney through tubulo-interstitial kidney disease","volume":"5","author":"Izzi","year":"2020","journal-title":"Kidney Int Rep"},{"key":"B10","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1530\/JME-20-0339","article-title":"MafA, NeuroD1 and HNF1\u03b2 synergistically activate the Slc2a2 (Glut2) gene in \u03b2-cells","volume":"67","author":"Ono","year":"2021","journal-title":"J Mol Endocrinol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1111\/jdi.14405","article-title":"ERK1\/2 gene expression and hypomethylation of Alu and LINE1 elements in patients with type 2 diabetes with and without cataract: Impact of hyperglycemia-induced oxidative stress","volume":"16","author":"Zeinali Nia","year":"2025","journal-title":"J Diabetes Investig"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2021.07.018","article-title":"Modeling HNF1B-associated monogenic diabetes using human iPSCs reveals an early stage impairment of the pancreatic developmental program","volume":"16","author":"El-Khairi","year":"2021","journal-title":"Stem Cell Rep"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2003.00903.x","article-title":"Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1beta gene mutation","volume":"63","author":"Bingham","year":"2003","journal-title":"Kidney Int"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2014.232","article-title":"HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum","volume":"11","author":"Clissold","year":"2015","journal-title":"Nat Rev Nephrol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.22.010305.104340","article-title":"The cellular basis of kidney development","volume":"22","author":"Dressler","year":"2006","journal-title":"Annu Rev Cell Dev Biol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-2277.2012.01458.x","article-title":"Maturity onset diabetes of the young: clinical characteristics and outcome after kidney and pancreas transplantation in MODY3 and RCAD patients: a single center experience","volume":"25","author":"Poitou","year":"2012","journal-title":"Transpl Int"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2024.150803","article-title":"A novel mutation in HNF1B promotes ferroptosis-mediated renal mesangial cells fibrosis","volume":"736","author":"Chen","year":"2024","journal-title":"Biochem Biophys Res Commun"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1155\/pedi\/4035026","article-title":"Revealing monogenic diabetes: clinical and genetic features of pediatric MODY cases in T\u00fcrkiye: single center experience","volume":"2025","author":"Sanri","year":"2025","journal-title":"Pediatr Diabetes"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/pedi.12959","article-title":"A cross-sectional study of patients referred for HNF1B-MODY genetic testing due to cystic kidneys and diabetes","volume":"21","author":"Sztromwasser","year":"2020","journal-title":"Pediatr Diabetes"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015050544","article-title":"Hepatocyte nuclear factor 1\u03b2-associated kidney disease: more than renal cysts and diabetes","volume":"27","author":"Verhave","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1136\/bmjdrc-2024-004885","article-title":"GLP-1 RA and dual GIP\/GLP-1 RA treatment in MODY: a descriptive case series","volume":"13","author":"Mehdi","year":"2025","journal-title":"BMJ Open Diabetes Res Care"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1777094\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T04:27:22Z","timestamp":1775795242000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1777094\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,10]]},"references-count":21,"alternative-id":["10.3389\/fendo.2026.1777094"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1777094","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,10]]},"article-number":"1777094"}}