Proteomics

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Mutations and variants of ONECUT1 in diabetes


ABSTRACT: Genes involved in distinct diabetes types suggest shared disease mechanisms. We show that rare ONECUT1 coding variants cause monogenic recessive diabetes (neonatal or very early-onset, syndromic) in two unrelated patients, and monogenic dominant diabetes (early adult-onset) in heterozygous relatives of these and 13 additional unrelated cases. Patients heterozygous for rare ONECUT1 coding variants define a subgroup of T2D with early-onset diabetes and other features. In addition, common regulatory ONECUT1 variants are associated with multifactorial T2D. Directed differentiation of human pluripotent stem cells to the pancreatic lineage revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. We uncovered that ONECUT1 activates the pro-endocrine genes NKX6.1 and NKX2.2 through binding to their cis-regulatory elements. Globally, ONECUT1-directed gene transcription occurs in association with major islet transcription factors, at clusters of pancreas- and endocrine-specific enhancers within open chromatin. ONECUT1 regulates a transcriptional and epigenetic machinery critical for proper endocrine pancreatic development, involved in a spectrum of diabetes, monogenic recessive and dominant, and multifactorial.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Stem Cell

SUBMITTER: Johannes Krumm  

LAB HEAD: Bernhard Kuster

PROVIDER: PXD018887 | Pride | 2021-11-03

REPOSITORIES: Pride

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Mutations and variants of ONECUT1 in diabetes.

Philippi Anne A   Heller Sandra S   Costa Ivan G IG   Senée Valérie V   Breunig Markus M   Li Zhijian Z   Kwon Gino G   Russell Ronan R   Illing Anett A   Lin Qiong Q   Hohwieler Meike M   Degavre Anne A   Zalloua Pierre P   Liebau Stefan S   Schuster Michael M   Krumm Johannes J   Zhang Xi X   Geusz Ryan R   Benthuysen Jacqueline R JR   Wang Allen A   Chiou Joshua J   Gaulton Kyle K   Neubauer Heike H   Simon Eric E   Klein Thomas T   Wagner Martin M   Nair Gopika G   Besse Céline C   Dandine-Roulland Claire C   Olaso Robert R   Deleuze Jean-François JF   Kuster Bernhard B   Hebrok Matthias M   Seufferlein Thomas T   Sander Maike M   Boehm Bernhard O BO   Oswald Franz F   Nicolino Marc M   Julier Cécile C   Kleger Alexander A  

Nature medicine 20211018 11


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, nonautoim  ...[more]

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