ESPEYB19 2. Antenatal and Neonatal Endocrinology Neonatal diabetes mellitus (6 abstracts)
2.14. Mutations and variants of ONECUT1 in diabetes
Philippi A , Heller S , Costa IG , Senée V , Breunig M , Li Z , Kwon G , Russell R , Illing A , Lin Q , Hohwieler M , Degavre A , Zalloua P , Liebau S , Schuster M , Krumm J , Zhang X , Geusz R , Benthuysen JR , Wang A , Chiou J , Gaulton K , Neubauer H , Simon E , Klein T , Wagner M , Nair G , Besse C , Dandine-Roulland C , Olaso R , Deleuze JF , Kuster B , Hebrok M , Seufferlein T , Sander M , Boehm BO , Oswald F , Nicolino M , Julier C & Kleger A
Nat Med. 2021 Nov;27(11):1928-1940. doi: 10.1038/s41591-021-01502-7. PMID: 34663987.
Brief Summary: This clinical study characterised the spectrum of novel diabetes phenotypes due to mutations in the Transcription factor One Cut Homeobox 1 (ONECUT1)/hepatocyte nuclear factor 6 (HNF6). The study uncovers novel forms of diabetes mellitus due to mutations in ONECUT1.
The One Cut Homeobox 1 (ONECUT1) transcription factor promotes differentiation of endocrine and duct cells of the pancreas (1). It is required for timely specification of the pancreas, controls expression of the ngn3 gene and acts upstream of Pdx-1 in the specification cascade in pancreatic development. In addition, it is essential for differentiation and morphogenesis of the biliary tract.
The authors identified homozygous loss of function mutations in the ONECUT1 transcription factor in 2 unrelated patients who had a syndromic form of permanent neonatal diabetes mellitus (with pancreatic hypoplasia and gallbladder agenesis/hypoplasia). Then they studied the heterozygous carriers of the mutation and noted that these carriers had a distinctive subgroup of diabetes mellitus with early-onset, non-autoimmune (antibody negative) diabetes which was responsive to treatment with oral medications such as oral sulphonylureas (a phenotype resembling Maturity Onset Diabetes of the Young, MODY). In addition, common regulatory ONECUT1 variants were associated with multifactorial type 2 diabetes.
To understand the molecular basis of the pancreatic hypoplasia and the diabetes mellitus, the authors generated induced pluripotent stem cells from the patients. Functional analysis of these induced pluripotent stem cells showed that the ONECUT1 mutations impair pancreatic progenitor formation and the subsequent endocrine program. ONECUT1 mutations led to altered binding of the transcription factor and affected the enhancer activity of other key pancreatic transcription factors such as NKX2.2/NKX6.1 in pancreatic progenitor cells.
This study has uncovered novel forms of diabetes mellitus due to homozygous and heterozygous mutations in the ONECUT1 transcription factor. This transcription factor has a pivotal role in the developmental and function of the pancreas and defects lead to broad spectrum of diabetes phenotypes depending in the type of mutation. It controls a transcriptional and epigenetic machinery regulating endocrine development.
Reference: 1. Jacquemin P, Durviaux SM, Jensen J, Godfraind C, Gradwohl G, Guillemot F, Madsen OD, Carmeliet P, Dewerchin M, Collen D, Rousseau GG, Lemaigre FP. Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn 3. Mol Cell Biol. 2000 Jun;20(12):4445-54. doi: 10.1128/MCB.20.12.4445-4454.2000. PMID: 10825208; PMCID: PMC85812.
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ESPE Yearbook of Paediatric Endocrinology
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