Abstract
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.
Highlights
Monogenic diabetes is a heterogeneous group of diseases caused by loss of function of single genes important for pancreatic beta cell function, survival or peripheral insulin action [1, 2]
In all four cases the miRNA expression level was lower in HNF1B-MODY than in all other tested groups
The cellular expression pattern of miRNA was consistent with serum levels, as all were significantly higher in HNF1α- than in HNF1β-deficient HepG2 cells
Summary
Monogenic diabetes is a heterogeneous group of diseases caused by loss of function of single genes important for pancreatic beta cell function, survival or peripheral insulin action [1, 2]. HNF1B-MODY (or MODY5 [5]), is caused by dominant mutations of the gene encoding hepatocyte nuclear factor 1 beta (HNF1β), a POU-family transcription factor (TF) necessary for proper development of pancreatic beta cells and kidneys [6]. If miRNA expression profiles vary at cellular levels, one could assume that their serum levels are altered, as serum miRNAs originate from active secretion by cells or as a consequence of cell death [10]. This prompted us to search for an miRNA whose expression would be altered in HNF1B-MODY. If an HNF1B-MODY-specific miRNA expression pattern could be identified, it could bolster the current diagnostic strategies of monogenic diabetes, which involve the application of statistical tools to stratify candidates for genetic screening
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
