Identification of circulating microRNAs in HNF1A-MODY carriers

Bonner, Caroline; Nyhan, Kristine C.; Bacon, Siobhán; Kyithar, M. P.; Schmid, Jasmin; Concannon, Caoimhín G.; Bray, Isabella; Stallings, Raymond L.; Prehn, Jochen H.M.; Byrne, Maria

doi:10.1007/s00125-013-2939-4

Cited by 27 publications

(28 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…42 In that study, two miRNAs, miR-103 and miR-224, were significantly upregulated upon suppression of endogenous HNF-1α function in the INS-1 cell line, and both miRNAs were found to be strongly elevated in the serum of HNF1A/MODY3 patients compared with family controls (mean levels 47-and 293-fold higher, respectively). 42 Furthermore, miR-103 may distinguish HNF1A/MODY3 patients from HbA1c-matched T2D subjects. Both miR-103 and miR-224 were further assessed in urine samples of a large cohort of HNF1A/ MODY3 mutation carriers (and of other types of diabetes, including T1D samples) and were found to be differentially highly expressed in HNF1A/MODY3 samples; miR-224 was also highly expressed in the urine of T1D patients, which could support its detection as a biomarker of β-cell demise, whereas high expression of miR-103 was found in all participants with diabetes, 43 which is consistent with the results of a recent metaanalysis that ranked miR-103 as one of the consistently deregulated miRNA in diabetes across multiple tissues including pancreas, adipose tissue and serum.…”

Section: Precision Medicine and Clinical Implementation Of Genomic Rementioning

confidence: 84%

“…Other circulating molecules, such as microRNAs (miRNAs) and long non‐coding RNAs (lncRNAs), are potent regulators of the expression of genes potentially involved in pancreatic development and β‐cell differentiation, as well as insulin production, secretion, and action, although lncRNAs have essentially been studied in cancer research . One representative study investigated changes in miRNA expression in INS‐1 insulinoma cells in which expression of the HNF1A ‐Pro291fsinsC hot‐spot mutation had been induced and in serum from 31 patients with HNF1A /MODY3 . In that study, two miRNAs, miR‐103 and miR‐224, were significantly upregulated upon suppression of endogenous HNF‐1α function in the INS‐1 cell line, and both miRNAs were found to be strongly elevated in the serum of HNF1A /MODY3 patients compared with family controls (mean levels 47‐ and 293‐fold higher, respectively) .…”

Section: Precision Medicine and Clinical Implementation Of Genomic Rementioning

confidence: 99%

“…One representative study investigated changes in miRNA expression in INS‐1 insulinoma cells in which expression of the HNF1A ‐Pro291fsinsC hot‐spot mutation had been induced and in serum from 31 patients with HNF1A /MODY3 . In that study, two miRNAs, miR‐103 and miR‐224, were significantly upregulated upon suppression of endogenous HNF‐1α function in the INS‐1 cell line, and both miRNAs were found to be strongly elevated in the serum of HNF1A /MODY3 patients compared with family controls (mean levels 47‐ and 293‐fold higher, respectively) . Furthermore, miR‐103 may distinguish HNF1A /MODY3 patients from HbA1c‐matched T2D subjects.…”

Section: Precision Medicine and Clinical Implementation Of Genomic Rementioning

confidence: 99%

See 2 more Smart Citations

Monogenic diabetes: Implementation of translational genomic research towards precision medicine

Vaxillaire

Froguel

2016

Journal of Diabetes

View full text Add to dashboard Cite

Various forms of early-onset non-autoimmune diabetes are recognized as monogenic diseases, each subtype being caused by a single highly penetrant gene defect at the individual level. Monogenic diabetes (MD) is clinically and genetically heterogeneous, including maturity-onset diabetes of the young (MODY), infancy-onset and neonatal diabetes mellitus, which are characterized by functional defects of insulin-producing pancreatic -cells and hyperglycemia early in life. Depending on the genetic cause, MD differs in ages at diabetes onset, the severity of hyperglycemia, long-term diabetic complications and extra-pancreatic manifestations. In this review, we discuss the many challenges of molecular genetic diagnosis of MD in the face of a substantial genetic heterogeneity; as well as the clinical benefit and cost-effectiveness of an early genetic diagnosis as demonstrated by simulation models based on lifetime complications and treatment costs. We also discuss striking examples of proof-of-concept of genomic medicine, which enabled to remarkably improve patients' care and long-term evolution. Recent advances in genome editing and pluripotent stem-cell reprogramming technologies provide new opportunities for in vitro diabetes modelling and the discovery of novel drug targets and cell-based diabetes therapies. A review of these future directions makes the case for exciting translational research for further understanding early-onset diabetes pathophysiology. Keywords:Diabetes, Genetics, Genomic medicine, Insulin secretion, Monogenic diabetes, MODY, Mutation, Next-generation sequencing, pancreatic -cell.This article is protected by copyright. All rights reserved. Genetic subtypes and clinical spectrum of monogenic diabetesMonogenic diabetes (MD) is caused by a rare single-gene defect that strongly contributes to the disease phenotype without or not much environmental contribution (meaning that is each individual DNA mutation or genome structural abnormality has a high or almost complete penetrance).1 MD encompasses a broad spectrum of clinically and genetically highly heterogeneous forms of nonautoimmune diabetes, which are mainly characterized by functional defects of pancreatic -cells resulting in insulin deficiency and moderate to severe hyperglycemia early in life. 1,2 MD includes maturity-onset diabetes of the young (MODY), early-infancy onset and neonatal diabetes mellitus (NDM), and many rare forms of atypical diabetes. [1][2][3] Decades of genetic and clinical research to decipher etiological mechanisms underlying MODY, NDM and early-infancy diabetes led to identify major genes and molecular pathways relevant to -cell physiology, that allowed to better understand the sustained genetic and clinical heterogeneity among the different MD subtypes in young people. MODY subtypesMODY usually presents in lean young individuals before age 25-30 years, as a dominantly inherited familial form of diabetes, and it may account for at least ~1-2% of all cases with type 2 diabetes. 4,5Epidemiology of MODY. Although M...

show abstract

Section: Precision Medicine and Clinical Implementation Of Genomic Rementioning

confidence: 84%

Section: Precision Medicine and Clinical Implementation Of Genomic Rementioning

confidence: 99%

Section: Precision Medicine and Clinical Implementation Of Genomic Rementioning

confidence: 99%

See 1 more Smart Citation

Monogenic diabetes: Implementation of translational genomic research towards precision medicine

Vaxillaire

Froguel

2016

Journal of Diabetes

View full text Add to dashboard Cite

show abstract

“…MODY is now classified in the group of “genetic defect in beta-cell function” with a subclassification according to the gene involved [105]. The most common mutation in the gene encoding transcription factor 1 (TCF-1)/hepatocyte nuclear factor 1a (HNF1A) that causes MODY3 is a frame shift mutation in exon 4, Pro291fsinsC-HNF1A [105–107]. The mutation within the gene results in a truncated protein that plays as a dominant negative action.…”

Section: Mirnas Associated With Beta-cell Dysfunction Under Diabetmentioning

confidence: 99%

“…Impaired insulin secretion caused by the mutated protein is associated with an elevation in the levels of miR-103 and miR-224. Thus, genetic variation may impact the expression of miRNAs, potentially synergizing with environmental stressors in triggering islet beta-cell dysfunction in diabetes [107]. …”

Section: Mirnas Associated With Beta-cell Dysfunction Under Diabetmentioning

confidence: 99%

Role of MicroRNAs in Islet Beta-Cell Compensation and Failure during Diabetes

Plaisance

Waeber

Regazzi

et al. 2014

Journal of Diabetes Research

View full text Add to dashboard Cite

Pancreatic beta-cell function and mass are markedly adaptive to compensate for the changes in insulin requirement observed during several situations such as pregnancy, obesity, glucocorticoids excess, or administration. This requires a beta-cell compensation which is achieved through a gain of beta-cell mass and function. Elucidating the physiological mechanisms that promote functional beta-cell mass expansion and that protect cells against death, is a key therapeutic target for diabetes. In this respect, several recent studies have emphasized the instrumental role of microRNAs in the control of beta-cell function. MicroRNAs are negative regulators of gene expression, and are pivotal for the control of beta-cell proliferation, function, and survival. On the one hand, changes in specific microRNA levels have been associated with beta-cell compensation and are triggered by hormones or bioactive peptides that promote beta-cell survival and function. Conversely, modifications in the expression of other specific microRNAs contribute to beta-cell dysfunction and death elicited by diabetogenic factors including, cytokines, chronic hyperlipidemia, hyperglycemia, and oxidized LDL. This review underlines the importance of targeting the microRNA network for future innovative therapies aiming at preventing the beta-cell decline in diabetes.

show abstract

Differential regulation of serum microRNA expression by HNF1β and HNF1α transcription factors

et al. 2016

View full text Add to dashboard Cite

Aims/hypothesisWe aimed to identify microRNAs (miRNAs) under transcriptional control of the HNF1β transcription factor, and investigate whether its effect manifests in serum.MethodsThe Polish cohort (N = 60) consisted of 11 patients with HNF1B-MODY, 17 with HNF1A-MODY, 13 with GCK-MODY, an HbA1c-matched type 1 diabetic group (n = 9) and ten healthy controls. Replication was performed in 61 clinically-matched British patients mirroring the groups in the Polish cohort. The Polish cohort underwent miRNA serum level profiling with quantitative real-time PCR (qPCR) arrays to identify differentially expressed miRNAs. Validation was performed using qPCR. To determine whether serum content reflects alterations at a cellular level, we quantified miRNA levels in a human hepatocyte cell line (HepG2) with small interfering RNA knockdowns of HNF1α or HNF1β.ResultsSignificant differences (adjusted p < 0.05) were noted for 11 miRNAs. Five of them differed between HNF1A-MODY and HNF1B-MODY, and, amongst those, four (miR-24, miR-27b, miR-223 and miR-199a) showed HNF1B-MODY-specific expression levels in the replication group. In all four cases the miRNA expression level was lower in HNF1B-MODY than in all other tested groups. Areas under the receiver operating characteristic curves ranged from 0.79 to 0.86, with sensitivity and specificity reaching 91.7% (miR-24) and 82.1% (miR-199a), respectively. The cellular expression pattern of miRNA was consistent with serum levels, as all were significantly higher in HNF1α- than in HNF1β-deficient HepG2 cells.Conclusions/interpretationWe have shown that expression of specific miRNAs depends on HNF1β function. The impact of HNF1β deficiency was evidenced at serum level, making HNF1β-dependent miRNAs potentially applicable in the diagnosis of HNF1B-MODY.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3945-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

show abstract

Identification of circulating microRNAs in HNF1A-MODY carriers

Abstract: Our study demonstrates that the pathophysiology of HNF1A-MODY is associated with the overexpression of miR-103 and miR-224. Furthermore, our study demonstrates that these miRNAs can be readily detected in the serum of HNF1A-MODY carriers.

Cited by 27 publications

References 46 publications

Monogenic diabetes: Implementation of translational genomic research towards precision medicine

Monogenic diabetes: Implementation of translational genomic research towards precision medicine

Role of MicroRNAs in Islet Beta-Cell Compensation and Failure during Diabetes

Differential regulation of serum microRNA expression by HNF1β and HNF1α transcription factors

Contact Info

Product

Resources

About