|
1
|
Bhattacharya S, Fernandez CJ, Kamrul-Hasan ABM, Pappachan JM. Monogenic diabetes: An evidence-based clinical approach. World J Diabetes 2025; 16:104787. [DOI: 10.4239/wjd.v16.i5.104787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/20/2025] [Accepted: 03/11/2025] [Indexed: 04/25/2025] Open
Abstract
Monogenic diabetes is a heterogeneous disorder characterized by hyperglycemia arising from defects in a single gene. Maturity-onset diabetes of the young (MODY) is the most common type with 14 subtypes, each linked to specific mutations affecting insulin synthesis, secretion and glucose regulation. Common traits across MODY subtypes include early-onset diabetes, a family history of autosomal dominant diabetes, lack of features of insulin resistance, and absent islet cell autoimmunity. Many cases are misdiagnosed as type 1 and type 2 diabetes mellitus. Biomarkers and scoring systems can help identify candidates for genetic testing. GCK-MODY, a common subtype, manifests as mild hyperglycemia and doesn’t require treatment except during pregnancy. In contrast, mutations in HNF4A, HNF1A, and HNF1B genes lead to progressive beta-cell failure and similar risks of complications as type 2 diabetes mellitus. Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes that usually presents within the first six months. Half of the cases are lifelong, while others experience transient remission. Permanent NDM is most commonly due to activating mutations in genes encoding the adenosine triphosphate-sensitive potassium channel (KCNJ11 or ABCC8) and can be transitioned to sulfonylurea after confirmation of diagnosis. Thus, in many cases, monogenic diabetes offers an opportunity to provide precision treatment. The scope has broadened with next-generation sequencing (NGS) technologies, replacing older methods like Sanger sequencing. NGS can be for targeted gene panels, whole-exome sequencing (WES), or whole-genome sequencing. Targeted gene panels offer specific information efficiently, while WES provides comprehensive data but comes with bioinformatic challenges. The surge in testing has also led to an increase in variants of unknown significance (VUS). Deciding whether VUS is disease-causing or benign can be challenging. Computational models, functional studies, and clinical knowledge help to determine pathogenicity. Advances in genetic testing technologies offer hope for improved diagnosis and personalized treatment but also raise concerns about interpretation and ethics.
Collapse
Affiliation(s)
| | - Cornelius J Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, Lincolnshire, United Kingdom
| | | | - Joseph M Pappachan
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, Greater Manchester, United Kingdom
- Department of Endocrinology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India
| |
Collapse
|
|
2
|
Merz S, Senée V, Philippi A, Oswald F, Shaigan M, Führer M, Drewes C, Allgöwer C, Öllinger R, Heni M, Boland A, Deleuze JF, Birkhofer F, Gusmao EG, Wagner M, Hohwieler M, Breunig M, Rad R, Siebert R, Messerer DAC, Costa IG, Alvarez F, Julier C, Kleger A, Heller S. A ONECUT1 regulatory, non-coding region in pancreatic development and diabetes. Cell Rep 2024; 43:114853. [PMID: 39427318 DOI: 10.1016/j.celrep.2024.114853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 08/25/2024] [Accepted: 09/24/2024] [Indexed: 10/22/2024] Open
Abstract
In a patient with permanent neonatal syndromic diabetes clinically similar to cases with ONECUT1 biallelic mutations, we identified a disease-causing deletion located upstream of ONECUT1. Through genetic, genomic, and functional studies, we identified a crucial regulatory region acting as an enhancer of ONECUT1 specifically during pancreatic development. This enhancer region contains a low-frequency variant showing a strong association with type 2 diabetes and other glycemic traits, thus extending the contribution of this region to common forms of diabetes. Clinical relevance is provided by experimentally tailored therapy options for patients carrying ONECUT1 coding or regulatory mutations.
Collapse
Affiliation(s)
- Sarah Merz
- Institute of Molecular Oncology and Stem Cell Biology, Ulm University Hospital, Ulm, Germany
| | - Valérie Senée
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France
| | - Anne Philippi
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France
| | - Franz Oswald
- Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany
| | - Mina Shaigan
- Institute for Computational Genomics, RWTH Aachen University Medical School, Aachen, Germany
| | - Marita Führer
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and University Hospital Ulm, Ulm, Germany
| | - Cosima Drewes
- Institute of Human Genetics, Ulm University & Ulm University Medical Center, Ulm, Germany
| | - Chantal Allgöwer
- Institute of Molecular Oncology and Stem Cell Biology, Ulm University Hospital, Ulm, Germany
| | - Rupert Öllinger
- Institute of Molecular Oncology and Functional Genomics, Center for Translational Cancer Research and Department of Medicine II, School of Medicine, Technical University of Munich, Munich, Germany
| | - Martin Heni
- Division of Endocrinology and Diabetology, Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany; Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Anne Boland
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Evry, France
| | - Jean-François Deleuze
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Evry, France
| | - Franziska Birkhofer
- Institute of Molecular Oncology and Stem Cell Biology, Ulm University Hospital, Ulm, Germany
| | - Eduardo G Gusmao
- Centre of Informatics, Federal University of Pernambuco, Recife, Brazil
| | - Martin Wagner
- Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany
| | - Meike Hohwieler
- Institute of Molecular Oncology and Stem Cell Biology, Ulm University Hospital, Ulm, Germany
| | - Markus Breunig
- Institute of Molecular Oncology and Stem Cell Biology, Ulm University Hospital, Ulm, Germany
| | - Roland Rad
- Institute of Molecular Oncology and Functional Genomics, Center for Translational Cancer Research and Department of Medicine II, School of Medicine, Technical University of Munich, Munich, Germany
| | - Reiner Siebert
- Institute of Human Genetics, Ulm University & Ulm University Medical Center, Ulm, Germany
| | - David Alexander Christian Messerer
- Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and University Hospital Ulm, Ulm, Germany; Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany
| | - Ivan G Costa
- Institute for Computational Genomics, RWTH Aachen University Medical School, Aachen, Germany
| | - Fernando Alvarez
- Division of Gastroenterology, Hepatology & Nutrition, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada
| | - Cécile Julier
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France.
| | - Alexander Kleger
- Institute of Molecular Oncology and Stem Cell Biology, Ulm University Hospital, Ulm, Germany; Division of Interdisciplinary Pancreatology, Department of Internal Medicine 1, Ulm University Hospital, Ulm, Germany; Core Facility Organoids, Ulm University, Ulm, Germany.
| | - Sandra Heller
- Institute of Molecular Oncology and Stem Cell Biology, Ulm University Hospital, Ulm, Germany.
| |
Collapse
|
|
3
|
Bhattacharya S, Pappachan JM. Monogenic diabetes in children: An underdiagnosed and poorly managed clinical dilemma. World J Diabetes 2024; 15:1051-1059. [PMID: 38983823 PMCID: PMC11229976 DOI: 10.4239/wjd.v15.i6.1051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 03/06/2024] [Accepted: 04/22/2024] [Indexed: 06/11/2024] Open
Abstract
Monogenic diabetes, constituting 1%-2% of global diabetes cases, arises from single gene defects with distinctive inheritance patterns. Despite over 50 ass-ociated genetic disorders, accurate diagnoses and management of monogenic diabetes remain inadequate, underscoring insufficient clinician awareness. The disease spectrum encompasses maturity-onset diabetes of the young (MODY), characterized by distinct genetic mutations affecting insulin secretion, and neonatal diabetes mellitus (NDM) - a heterogeneous group of severe hyperglycemic disorders in infants. Mitochondrial diabetes, autoimmune monogenic diabetes, genetic insulin resistance and lipodystrophy syndromes further diversify the monogenic diabetes landscape. A tailored approach based on phenotypic and biochemical factors to identify candidates for genetic screening is recommended for suspected cases of MODY. NDM diagnosis warrants immediate molecular genetic testing for infants under six months. Identifying these genetic defects presents a unique opportunity for precision medicine. Ongoing research aimed to develop cost-effective genetic testing methods and gene-based therapy can facilitate appropriate identification and optimize clinical outcomes. Identification and study of new genes offer a valuable opportunity to gain deeper insights into pancreatic cell biology and the pathogenic mechanisms underlying common forms of diabetes. The clinical review published in the recent issue of World Journal of Diabetes is such an attempt to fill-in our knowledge gap about this enigmatic disease.
Collapse
Affiliation(s)
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom
| |
Collapse
|
|
4
|
Heller S, Li Z, Lin Q, Geusz R, Breunig M, Hohwieler M, Zhang X, Nair GG, Seufferlein T, Hebrok M, Sander M, Julier C, Kleger A, Costa IG. Transcriptional changes and the role of ONECUT1 in hPSC pancreatic differentiation. Commun Biol 2021; 4:1298. [PMID: 34789845 PMCID: PMC8599846 DOI: 10.1038/s42003-021-02818-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 10/24/2021] [Indexed: 02/07/2023] Open
Abstract
Cell type specification during pancreatic development is tightly controlled by a transcriptional and epigenetic network. The precise role of most transcription factors, however, has been only described in mice. To convey such concepts to human pancreatic development, alternative model systems such as pancreatic in vitro differentiation of human pluripotent stem cells can be employed. Here, we analyzed stage-specific RNA-, ChIP-, and ATAC-sequencing data to dissect transcriptional and regulatory mechanisms during pancreatic development. Transcriptome and open chromatin maps of pancreatic differentiation from human pluripotent stem cells provide a stage-specific pattern of known pancreatic transcription factors and indicate ONECUT1 as a crucial fate regulator in pancreas progenitors. Moreover, our data suggest that ONECUT1 is also involved in preparing pancreatic progenitors for later endocrine specification. The dissection of the transcriptional and regulatory circuitry revealed an important role for ONECUT1 within such network and will serve as resource to study human development and disease.
Collapse
Affiliation(s)
- Sandra Heller
- grid.410712.1Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Zhijian Li
- grid.1957.a0000 0001 0728 696XInstitute for Computational Genomics, RWTH Aachen University Medical School, Aachen, Germany
| | - Qiong Lin
- grid.420044.60000 0004 0374 4101Bayer AG, Research & Development, Pharmaceuticals, Bioinformatics, Berlin, Germany
| | - Ryan Geusz
- grid.266100.30000 0001 2107 4242Pediatric Diabetes Research Center (PDRC) at the University of California, San Diego, USA
| | - Markus Breunig
- grid.410712.1Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Meike Hohwieler
- grid.410712.1Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Xi Zhang
- grid.410712.1Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Gopika G. Nair
- grid.266102.10000 0001 2297 6811Diabetes Center at the University of California, San Francisco, USA
| | - Thomas Seufferlein
- grid.410712.1Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Matthias Hebrok
- grid.266102.10000 0001 2297 6811Diabetes Center at the University of California, San Francisco, USA
| | - Maike Sander
- grid.266100.30000 0001 2107 4242Pediatric Diabetes Research Center (PDRC) at the University of California, San Diego, USA
| | - Cécile Julier
- grid.4444.00000 0001 2112 9282Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR-8104, Paris, France
| | - Alexander Kleger
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany.
| | - Ivan G. Costa
- grid.1957.a0000 0001 0728 696XInstitute for Computational Genomics, RWTH Aachen University Medical School, Aachen, Germany
| |
Collapse
|
|
5
|
Mutations and variants of ONECUT1 in diabetes. Nat Med 2021; 27:1928-1940. [PMID: 34663987 DOI: 10.1038/s41591-021-01502-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 08/13/2021] [Indexed: 12/12/2022]
Abstract
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.
Collapse
|