Mutations and variants of ONECUT1 in diabetes

• DOI: 10.1038/s41591-021-01502-7
• Publication Date: 2021-10-19T00:13:50Z
• Authors: Anne Philippi; Sandra Heller; Ivan G. Costa; Valérie Senée; Markus Breunig; Zhijian Li; Gino Kwon; Ronan Russell; Anett Illing; Qiong Lin; Meike Hohwieler; Anne Degavre; Pierre Zalloua; Stefan Liebau; Michael Schuster; Johannes Krumm; Xi Zhang; Ryan Geusz; Jacqueline R. Ben...; Allen Wang; Joshua Chiou; Kyle Gaulton; Heike Neubauer; Eric Simon; Thomas Klein; Martin Wagner; Gopika Nair; Céline Besse; Claire Dandine-Ro...; Robert Olaso; Jean-François Del...; Bernhard Kuster; Matthias Hebrok; Thomas Seufferlein; Maike Sander; Bernhard O. Boehm; Franz Oswald; Marc Nicolino; Cécile Julier; Alexander Kleger
• Keywords: Male; Pluripotent Stem Cells; 0301 basic medicine; Multifactorial Inheritance; Biomedical and clinical sciences; Transcription, Genetic; Organogenesis; Immunology; 610; Regenerative Medicine; Autoimmune Disease; Medical and Health Sciences; Congenital Abnormalities; 03 medical and health sciences; Genetic; Clinical Research; [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]; Genetics; Diabetes Mellitus; 2.1 Biological and endogenous factors; Humans; Stem Cell Research - Embryonic - Human; Pancreas; Metabolic and endocrine; Pediatric; Homeodomain Proteins; [SDV.GEN]Life Sciences [q-bio]/Genetics; Fetal Growth Retardation; Biomedical and Clinical Sciences; Stem Cell Research - Induced Pluripotent Stem Cell - Human; Stem Cell Research - Induced Pluripotent Stem Cell; Diabetes; Infant, Newborn; Health sciences; Gallbladder; Infant; Pancreatic Diseases; Cell Differentiation; Stem Cell Research; Newborn; 3. Good health; Hepatocyte Nuclear Factor 6; Homeobox Protein Nkx-2.2; Diabetes Mellitus, Type 2; Transcription; Type 2

Genes involved in distinct diabetes types suggest shared disease mechanisms. Here we show that One Cut Homeobox 1 (ONECUT1) mutations cause monogenic recessive syndromic diabetes in two unrelated patients, characterized by intrauterine growth retardation, pancreas hypoplasia and gallbladder agenesis/hypoplasia, and early-onset diabetes in heterozygous relatives. Heterozygous carriers of rare coding variants of ONECUT1 define a distinctive subgroup of diabetic patients with early-onset, nonautoimmune diabetes, who respond well to diabetes treatment. In addition, common regulatory ONECUT1 variants are associated with multifactorial type 2 diabetes. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. Loss of ONECUT1 altered transcription factor binding and enhancer activity and NKX2.2/NKX6.1 expression in pancreatic progenitor cells. Collectively, we demonstrate that ONECUT1 controls a transcriptional and epigenetic machinery regulating endocrine development, involved in a spectrum of diabetes, encompassing monogenic (recessive and dominant) as well as multifactorial inheritance. Our findings highlight the broad contribution of ONECUT1 in diabetes pathogenesis, marking an important step toward precision diabetes medicine.