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Autor(en) / Beteiligte

Titel

Mutations and variants of ONECUT1 in diabetes

Ist Teil von

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

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.

Sprache: Englisch
Identifikatoren: ISSN: 1078-8956, 1546-170X
eISSN: 1546-170X
DOI: 10.1038/s41591-021-01502-7
Titel-ID: cdi_hal_primary_oai_HAL_cea_04359988v1

Format: –
Schlagworte: Age, Analysis, Biochemistry, Molecular Biology, Cell differentiation, Cell Differentiation - genetics, Congenital Abnormalities - genetics, Diabetes, Diabetes mellitus, Diabetes mellitus (non-insulin dependent), Diabetes Mellitus, Type 2 - genetics, Diabetes Mellitus, Type 2 - pathology, Diagnosis, Epigenetics, Fetal Growth Retardation - genetics, Gallbladder, Gallbladder - abnormalities, Gene mutations, Genetic aspects, Genetic diversity, Genetic variance, Genetics, Genomics, Growth rate, Health aspects, Hepatocyte Nuclear Factor 6 - genetics, Homeobox, Homeobox genes, Homeobox Protein Nkx-2.2 - biosynthesis, Homeodomain Proteins - biosynthesis, Homeotic genes, Humans, Hypoplasia, Infant, Infant, Newborn, Life Sciences, Male, Multifactorial Inheritance - genetics, Mutation, Neonates, Nkx2.2 protein, Nkx6.1 protein, Observations, Organogenesis - genetics, Pancreas, Pancreas - abnormalities, Pancreas - embryology, Pancreatic Diseases - congenital, Pancreatic Diseases - genetics, Pathogenesis, Patients, Phenotyping, Pluripotency, Pluripotent Stem Cells - cytology, Polygenic inheritance, Progenitor cells, Risk factors, Stem cells, Subgroups, Transcription, Genetic - genetics

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