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The\n                      <jats:italic>RFX6<\/jats:italic>\n                      variant p.His293LeufsTer7 is significantly enriched in the Finnish population, with almost 1:250 individuals as a carrier. Importantly, the FinnGen study indicates a high predisposition for heterozygous carriers to develop type 2 and gestational diabetes. However, the precise mechanism of this predisposition remains unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To understand the role of this variant in beta cell development and function, we used CRISPR technology to generate allelic series of pluripotent stem cells. We created two isogenic stem cell models: a human embryonic stem cell model; and a patient-derived stem cell model. Both were differentiated into pancreatic islet lineages (stem-cell-derived islets, SC-islets), followed by implantation in immunocompromised NOD-SCID-Gamma mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Stem cell models of the homozygous variant\n                      <jats:italic>RFX6<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      predictably failed to generate insulin-secreting pancreatic beta cells, mirroring the phenotype observed in Mitchell\u2013Riley syndrome. Notably, at the pancreatic endocrine stage, there was an upregulation of precursor markers\n                      <jats:italic>NEUROG3<\/jats:italic>\n                      and\n                      <jats:italic>SOX9<\/jats:italic>\n                      , accompanied by increased apoptosis. Intriguingly, heterozygous\n                      <jats:italic>RFX6<\/jats:italic>\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      SC-islets exhibited\n                      <jats:italic>RFX6<\/jats:italic>\n                      haploinsufficiency (54.2% reduction in protein expression), associated with reduced beta cell maturation markers, altered calcium signalling and impaired insulin secretion (62% and 54% reduction in basal and high glucose conditions, respectively). However,\n                      <jats:italic>RFX6<\/jats:italic>\n                      haploinsufficiency did not have an impact on beta cell number or insulin content. The reduced insulin secretion persisted after in vivo implantation in mice, aligning with the increased risk of variant carriers to develop diabetes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>\n                      Our allelic series isogenic SC-islet models represent a powerful tool to elucidate specific aetiologies of diabetes in humans, enabling the sensitive detection of aberrations in both beta cell development and function. We highlight the critical role of RFX6 in augmenting and maintaining the pancreatic progenitor pool, with an endocrine roadblock and increased cell death upon its loss. We demonstrate that\n                      <jats:italic>RFX6<\/jats:italic>\n                      haploinsufficiency does not affect beta cell number or insulin content but does impair function, predisposing heterozygous carriers of loss-of-function variants to diabetes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Data availability<\/jats:title>\n                    <jats:p>\n                      Ultra-deep bulk RNA-seq data for pancreatic differentiation stages 3, 5 and 7 of H1\n                      <jats:italic>RFX6<\/jats:italic>\n                      genotypes are deposited in the Gene Expression Omnibus database with accession code GSE234289. Original western blot images are deposited at Mendeley (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/data.mendeley.com\/datasets\/g75drr3mgw\/2\">https:\/\/data.mendeley.com\/datasets\/g75drr3mgw\/2<\/jats:ext-link>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-024-06163-y","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T08:01:51Z","timestamp":1715673711000},"page":"1642-1662","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function"],"prefix":"10.1007","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0165-2660","authenticated-orcid":false,"given":"Hazem","family":"Ibrahim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4784-5452","authenticated-orcid":false,"given":"Diego","family":"Balboa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8865-7060","authenticated-orcid":false,"given":"Jonna","family":"Saarim\u00e4ki-Vire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0879-1807","authenticated-orcid":false,"given":"Hossam","family":"Montaser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1825-9793","authenticated-orcid":false,"given":"Oleg","family":"Dyachok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5994-5290","authenticated-orcid":false,"given":"Per-Eric","family":"Lund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8893-7348","authenticated-orcid":false,"given":"Muhmmad","family":"Omar-Hmeadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4089-8877","authenticated-orcid":false,"given":"Jouni","family":"Kvist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8670-7717","authenticated-orcid":false,"given":"Om 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Grym, A. Laitinen and R. Trokovic (Stem Cells and Metabolism Research Program, University of Helsinki) for their expert technical support. The quality control and library preparation of the RNA-seq samples were provided by the Biomedicum Functional Genomics Unit at the Helsinki Institute of Life Science and Biocenter Finland at the University of Helsinki. Novaseq sequencing was performed by the Sequencing laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki. The graphical abstract was generated using BioRender. We are grateful to the family of the Mitchell\u2013Riley syndrome patient for participating and we want to acknowledge the participants and investigators of the FinnGen study. The following biobanks are acknowledged for delivering biobank samples to FinnGen: Auria Biobank; THL Biobank; Helsinki Biobank; Biobank Borealis of Northern Finland; Finnish Clinical Biobank Tampere; Biobank of Eastern Finland; Central Finland Biobank; Finnish Red Cross Blood Service Biobank; Terveystalo Biobank; and Arctic Biobank. All Finnish Biobanks are members of BBMRI infrastructure. Finnish Biobank Cooperative (FINBB) is the coordinator of BBMRI-ERIC operations in Finland. The Finnish biobank data can be accessed through the Fingenious\u00ae services managed by FINBB.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"Ultra-deep bulk RNA-seq data for pancreatic differentiation stages 3, 5 and 7 of H1 <i>RFX6<\/i> genotypes are deposited in the Gene Expression Omnibus database with accession code GSE234289. Original western blot images are deposited at Mendeley (\n                      \n                      ). Any additional information required to reanalyse the data reported in this paper is available from the corresponding authors on request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"TO acknowledges the funding provided by the Academy of Finland (MetaStem Center of Excellence grant 312437), the Novo Nordisk Foundation, the Sigrid Juselius Foundation and the Wellcome Collaborative Award in Science. HI acknowledges the funding provided by the Doctoral Programme in Biomedicine (DPBM), Orion Research Foundation, Paulon S\u00e4\u00e4ti\u00f6 Foundation, Diabetestutkimuss\u00e4\u00e4ti\u00f6 Foundation, Biomedicum Helsinki Foundation, the Finnish Cultural Foundation and Magnus Ehrnrooth Foundation. AT acknowledges project grants from the Swedish Research Council, Novo Nordisk Foundation, Diabetes Wellness Sverige, the Swedish Diabetes Foundation, Barndiabetesfonden, Family Ernfors Foundation and the strategic grant consortium Excellence of Diabetes Research in Sweden (EXODIAB). The FinnGen project is funded by two grants from Business Finland (HUS 4685\/31\/2016 and UH 4386\/31\/2016) and the following industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation & Celgene International II S\u00e0rl), Genentech Inc., Merck Sharp & Dohme LCC, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, Novartis AG and Boehringer Ingelheim International GmbH. The study sponsor\/funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"HI conceived and conceptualised the study, generated the H1 hESCs lines, standardised the differentiation protocols, performed the experiments, analysed data and wrote the original manuscript. DB and SE generated the iPSCs corrected cell lines and DB participated in manuscript writing. SE participated in generating the genetically edited clones, RNA purification and RT-qPCR experiments. JSV and HM performed and analysed animal experiments. MOH, OD and PEL performed and analysed cell electrophysiology experiments. JK analysed the bulk RNA-seq datasets and participated in manuscript writing. OPD and TT analysed and interpreted the FinnGen data , also participated in manuscript writing. VL conducted the morphometric analyses pipelines. TB and VC participated in analysis and manuscript writing. JU performed the insulin and C-peptide ELISA measurements. PJM is the paediatric endocrinologist in charge of the individual patient. SB and AT conceptualised the cell electrophysiology experiments and participated in the analysis and interpretation of the data and in manuscript writing. TO conceived and supervised the study, provided resources, acquired funding and participated in manuscript writing. All authors made contributions to reviewing the final version of the manuscript and approved it. HI is responsible for the integrity of the work as a whole.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}