Ibrahim, Hazem http://orcid.org/0000-0003-0165-2660
Balboa, Diego http://orcid.org/0000-0002-4784-5452
Saarimäki-Vire, Jonna http://orcid.org/0000-0002-8865-7060
Montaser, Hossam http://orcid.org/0000-0003-0879-1807
Dyachok, Oleg http://orcid.org/0000-0003-1825-9793
Lund, Per-Eric http://orcid.org/0000-0002-5994-5290
Omar-Hmeadi, Muhmmad http://orcid.org/0000-0001-8893-7348
Kvist, Jouni http://orcid.org/0000-0002-4089-8877
Dwivedi, Om P. http://orcid.org/0000-0001-8670-7717
Lithovius, Väinö http://orcid.org/0000-0002-1537-5548
Barsby, Tom http://orcid.org/0000-0002-9657-1371
Chandra, Vikash http://orcid.org/0000-0002-2713-1831
Eurola, Solja http://orcid.org/0009-0007-8025-7197
Ustinov, Jarkko
Tuomi, Tiinamaija http://orcid.org/0000-0002-8306-6202
Miettinen, Päivi J. http://orcid.org/0000-0002-5184-9616
Barg, Sebastian http://orcid.org/0000-0003-4661-5724
Tengholm, Anders http://orcid.org/0000-0003-4508-0836
Otonkoski, Timo http://orcid.org/0000-0001-9190-2496
Funding for this research was provided by:
Excellence of Diabetes Research in Sweden
Svenska Diabetesstiftelsen
Biomedicum Helsinki-säätiö
Barndiabetesfonden
Suomen Kulttuurirahasto
Research Council of Finland
Magnus Ehrnroothin Säätiö
Svenska Forskningsrådet Formas
Paulon Säätiö
Diabetestutkimussäätiö
Novo Nordisk Fonden
Insamlingsstiftelsen Diabetes Wellness Network Sverige
Stiftelsen Familjen Ernfors Fond
Sigrid Juséliuksen Säätiö
Orionin Tutkimussäätiö
University of Helsinki
Article History
Received: 8 December 2023
Accepted: 21 March 2024
First Online: 14 May 2024
Acknowledgements
: We thank H. 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–Riley 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® services managed by FINBB.
: 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 (). Any additional information required to reanalyse the data reported in this paper is available from the corresponding authors on request.
: 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 Säätiö Foundation, Diabetestutkimussäätiö 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 Sàrl), 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.
: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.
: 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.