Personalized medicine in diabetes: Unraveling the disease casualty of HNF1A and HNF4A gene coding variants of “unknown clinical significance” in two large Norwegian diabetes registries
Unraveling the disease casualty of HNF1A and HNF4A gene coding variants in two large Norwegian diabetes registries
This report represents my progress as a PhD candidate from April 2016 to December 2016. It also gives a summary of my PhD project, describing some of the scientific results that have been achieved so far.
Maturity-onset Diabetes of the Young (MODY) is a monogenic form of diabetes which represents 2-3 % of all diabetes cases in Norway. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1-alpha (HNF-1A, MODY3) and hepatocyte nuclear factor 4-alpha (HNF-4A, MODY1) are two of the most common MODY forms. Genetic testing is usually performed to identify previously reported genetic variants associated with the disease, and thereby the diagnosis of MODY is set. However, genetic variants that so far have not been associated with MODY and are not well described in the literature are also identified during genetic testing. These are then classified as variants of unknown significance. My PhD project aims therefore to functionally characterize HNF1A and HNF4A variants of “uncertain clinical significance”, in the two Norwegian Registries, and to correlate the findings with clinical characteristics of HNF1A/HNF4A variant carriers. This will be then used to verify a genetic diagnosis and allow alternative treatment strategies for these affected patients. To date there are 44 missense HNF1A variants and 11 missense HNF4A variants in the MODY Registry. Of these are 26 of HNF1A and 7 of HNF4A of unknown significance. In the Norwegian Childhood Registry there are 13 missense HNF1A variants and 4 missense HNF4A variants. Of these 9 HNF1A and all of HNF4A variants are of unknown significance. So far, I have carried out functional protein assays in order to investigate a possible pathogenic effect of the 15 HNF4A missense variants identified in the Norwegian MODY Registry and the Norwegian Childhood Diabetes Registry. Interestingly, I was able to identify one HNF4A variant found in both registries and classified as of unknown significance to be likely pathogenic. This spring, I am planning therefore to present my findings at the EASD study Group on Genetics of Diabetes meeting which will be organized in Leiden, May 11th - 13th, 2017. Ongoing studies are also carried out at the main to investigate other protein aspects affected by those variants. My future plan is to prepare a manuscript based on the findings and submitted preferably after this summer (fall 2017). In addition, my project aims to investigate new mechanisms for the regulation of HNF-1A, such as post translational modification (SUMOylation). So far, I have data showing for the first time that HNF-1A is a substrate for SUMOylation both in cellullo and in vitro. I have also found three SUMOylation sites in HNF-1A and shown that SUMOylation affects both the activity and stability of HNF-1A. All the gathered data indicate thus that SUMOylation of HNF-1A represents a novel post translational regulatory mechanism of HNF-1A in pancreatic ß–cells, most likely with implication for glucose-stimulated insulin secretion. Last fall, I was able to present those findings in two international conferences: the 52nd EASD Annual Meeting (Munich) and the Copenhagen Bioscience Conference, Protein Signaling- From pathways to Networks. The feedback I received at the conferences helped me to complete some of my experiments and strengthen my findings. I have a manuscript in preparation based on these findings ( Kaci et al., The transcriptional activity of the hepatocyte nuclear factor 1 alpha is regulated by the protein inhibitor of activated STAT (PIASy) ) which I plan to submit for publication at the beginning of this year (spring 2017).