Fig. 1.

Impact of heterozygous and homozygous RFX6 frameshift variant p.His293LeufsTer7 on diabetes development. (a) The human RFX6 gene and the encoded WT and predicted mutant proteins. The WT RFX6 is a 928-amino-acid protein containing a DNA binding domain (DBD) and three dimerisation domains (B, C and Dimerisation). The RFX6 frameshift variant p.His293LeufsTer7 contains the DBD, dimerisation domain B and a frameshift making an early stop codon at 298. The antibody used in this study binds to the amino acid sequence from 676–762 (shown in yellow). (b) Survival curve stratified by RFX6 genotype (WT, n=439,416 and Het; heterozygous carriers, n=1318) and adjusted HR for type 2 diabetes risk. The mean ± SD age at onset for Het and WT was 57.48±12.87 and 59.91±12.43 years, respectively (p=2.5×10⁻⁴). The total number of individuals in the FinnGen dataset was 440,734, which included 71,728 with type 2 diabetes. (c) Survival curve stratified by RFX6 genotype (WT, n=253,803 and Het; heterozygous carriers, n=814) and adjusted HR for gestational diabetes risk. The total number of individuals in the FinnGen dataset was 254,617, which included 16,802 with gestational diabetes. (d) Schematic showing the patient with Mitchell–Riley syndrome’s clinical manifestations (pancreatic hypoplasia with neonatal diabetes, gall bladder agenesis and intestinal stenosis with malabsorptive diarrhoea). (e) Schematic of generating RFX6 allelic series of the frameshift variant in H1 hESCs and patient-derived iPSCs, followed by directed differentiation into pancreatic endocrine cells. Panel (e) was created using Servier Medical Art. Survival plots (b, c) were generated using survminer and adjusted HRs were calculated using Cox proportional hazards model adjusting for age, sex and principal components PC1–PC10