R J Markert
A Conceptual, Practice-orientated Biometrics Course for Medical Students
Medical teacher
regulatory factor x 6 rfx6 crucial pancreatic endocrine development differentiation rfx6 variant phis293leufster7 significantly enriched finnish population almost 1250 individuals carrier importantly finngen study indicates high predisposition heterozygous carriers develop type 2 gestational diabetes however precise mechanism predisposition remains unknown understand role variant beta cell development function used crispr technology generate allelic series pluripotent stem cells created two isogenic stem cell models human embryonic stem cell model patientderived stem cell model differentiated pancreatic islet lineages stemcellderived islets scislets followed implantation immunocompromised nodscidgamma mice stem cell models homozygous variant rfx6 predictably failed generate insulinsecreting pancreatic beta cells mirroring phenotype observed mitchellriley syndrome notably pancreatic endocrine stage upregulation precursor markers neurog3 sox9 accompanied increased apoptosis intriguingly heterozygous rfx6 scislets exhibited rfx6 haploinsufficiency 542 reduction protein expression associated reduced beta cell maturation markers altered calcium signalling impaired insulin secretion 62 54 reduction basal high glucose conditions respectively however rfx6 haploinsufficiency impact beta cell number insulin content reduced insulin secretion persisted vivo implantation mice aligning increased risk variant carriers develop diabetes allelic series isogenic scislet models represent powerful tool elucidate specific aetiologies diabetes humans enabling sensitive detection aberrations beta cell development function highlight critical role rfx6 augmenting maintaining pancreatic progenitor pool endocrine roadblock increased cell death upon loss demonstrate rfx6 haploinsufficiency affect beta cell number insulin content impair function predisposing heterozygous carriers lossoffunction variants diabetes ultradeep bulk rnaseq data pancreatic differentiation stages 3 5 7 h1 rfx6 genotypes deposited gene expression omnibus database accession code gse234289 original western blot images deposited mendeley httpsdatamendeleycomdatasetsg75drr3mgw2