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June 23, 2023

Talk: The curious case of ADTKD-MUC1: Molecular, genetic, clinical, and therapeutic aspects of a rare kidney disease with high frequency in Cyprus | BioHIT - SKEL

BioHIT | Biomedical and Health Informatics Team of SKEL | The AI Lab will host invited speaker Dr Gregory Papagregoriou, lead scientist and a senior group leader at the Center of Excellence in Biobanking and Biomedical Research at the University of Cyprus (UCY), to deliver a talk titled The curious case of ADTKD-MUC1: Molecular, genetic, clinical, and therapeutic aspects of a rare kidney disease with high frequency in Cyprus, on Monday 3 July 2023, at 13:00 EEST. The talk will be held online via zoom.

For online participation:

Meeting ID: 884 2222 1195
Passcode: 483728

About the talk: Autosomal Dominant Tubulointerstitial Kidney Diseases (ADTKD) is a recently termed group of rare genetic diseases mainly characterised by interstitial nephritis, variable age at onset of end-stage renal disease (ESRD), bland urinary sediment, and no other associated features, except for progressive chronic kidney disease. Mutations in MUC1, UMOD, REN, HNF1B, and SEC61A1 have been associated with different types of ADTKD, and the mutated protein product in each case is considered to have a central role in disease pathogenesis, where cellular stress is found to be induced by improperly folded or misplaced proteins.  Caused by mutations in the MUC1 gene encoding for Mucin-1, ADTKD-MUC1 remains widely under-diagnosed as confident diagnosis is usually impeded by the lack of solid pathognomonic criteria, while the reasons affecting disease progression remain unknown. The most frequent genetic event triggering the disease is a frameshift mutation caused by a single C-insertion (27dupC) at the variable tandem repeat region (VNTR) of MUC1. Frameshift mutations in MUC1 cause the generation of a neo-peptide having a scrambled VNTR sequence and a premature stop codon. The underlying pathobiological mechanism of ADTKD-MUC1 involves defected trafficking of the frameshifted protein towards the lysosome, and its accumulation and aggregation into COPII/COPI type vesicles at the endoplasmic reticulum – Golgi intermediate compartment (ERGIC). BRD4780 is a therapeutic lead that appears to selectively clear the misfolded MUC1 protein from the cell, and is now considered as a putative treatment. The Molecular Medicine Research Center, University of Cyprus (MMRC, UCY) has been studying ADTKD-MUC1 for the past 30 years and was the first to discover the critical region on 1q21.1 where MUC1 was later identified to cause the disease. In Pafos Cyprus, resides a unique cohort of 163 27dupC ADTKD-MUC1 patients; notably, 27dup C has a frequency of 1:580 individuals living in Pafos. To describe the natural history of the disease and identify biomarkers, we follow a group of 46 patients and 29 related controls since 2018. Non-continuous clinical data going back >40 years were collected and processed to form a dataset using Euclidean distances in theoretical 6-month intervals from 18-80 years of age. A K-Means for longitudinal data (KML) was found to generate clinically relevant clusters, which were reviewed by a nephrologist. KML3D was used to incorporate two datasets of matched variables for clustering, the estimated glomerular filtration rate (eGFR, serum creatinine) and serum urea levels. Results show four progression groups ranging from 27dupC carriers with no symptoms, to patients progressing rapidly to ESRD. Clusters were used to describe disease manifestation and biomarker discovery, which involves the multi-omic profiling of urinary extracellular vesicles (uEVs) using transcriptomics, proteomics, metabolomics, and lipidomics. Besides biomarkers, this multileveled approach has also been used for drug discovery and drug vehicle development.

Short Bio: Dr Gregory Papagregoriou is the lead scientist and a senior group leader at the Center of Excellence in Biobanking and Biomedical Research at the University of Cyprus (UCY). He was appointed by the director of the CoE as a member of the Academic Council, and the Internal bioethics advisory board. He received his BSc in Biology at the Aristoteles University, Greece and his MRes degree in Medical and Molecular Biosciences with distinction from the Medical School of the University of Newcastle, UK. Dr Papagregoriou earned his PhD in Molecular Biology from UCY in 2012 on the involvement of microRNAs in modifying kidney disease manifestation through targeting dynamics of relevant genes, under the supervision of Prof. C. Deltas, for which he also gained an award for his academic and research performance from the faculty Dean. Dr. Papagregoriou worked on generating therapeutics for ADTKD-MUC1 at the Center for the Development of Therapeutics at the Broad Institute of MIT and Harvard, under Dr A. Greka at the Kidney Disease Initiative. His project involved exploiting results of high-content compound screening to discover disease biomarkers for prospective clinical trials and worked on the development of a mass spectrometry-based assay using urinary extracellular vesicles from patients, which was consequently validated in a biomarker clinical trial in Cyprus led by Dr Papagregoriou. At and the Molecular Medicine Research Center (MMRC, UCY) Dr Papagregoriou’s group focuses on developing biomarkers and studying the genetics of rare diseases, with a special interest in the molecular, clinical, and genetic basis of chronic kidney diseases. Regarding ADTKD-MUC1, he is working on extracellular vesicle cargo at a multi-omics level and their potential role as drug vehicles, while trying to decipher the clinical aspects of the disease by collecting and analyzing longitudinal data from patients. Having a deep understanding of human genetics, Dr Papagregoriou was the first person to set up and run an NGS facility in Cyprus at the MMRC, and since then he has designed, developed, and implemented research and diagnostic pipelines involving DNA (WES, gene, and SNP panels, cfDNA, ctDNA) and RNA (Transcriptomics, small RNAs) sequencing. More information at

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