Daan Panneman and Richard Rodenburg, theme Metabolic disorders, have been awarded a grant from Stichting Stofwisselkracht for their proposal entitled “CRISPR/Cas9 knock-in complementation in fibroblasts of mitochondrial disease patients”. Together with Omar Tutakhel and Jan Smeitink, they will investigate the possibility of using CRISPR/Cas9 knock-in to correct genetic variants in patient fibroblasts.
Mitochondrial disorders belong to the most frequently occurring metabolic disorders (incidence estimated 1:5000 live births). The disease onset can be at any age, involving different organs, and with a wide range of clinical signs and symptoms. Establishing a diagnosis is often challenging because of the large number of mitochondrial disease-causing genes (approximately 400 disease-causing genes described to date) and very limited genotype-phenotype correlations.
In the Radboud Center for Mitochondrial Medicine, Whole Exome Sequencing (WES) is used to identify pathogenic genetic variants in patients suspected of a mitochondrial disorder. Based on genetic, clinical, and biochemical data, a diagnosis is made. However, proving a causal relationship between the patient’s phenotype and genetic variants of unknown significance (VUS) is difficult. The current procedures for follow-up investigations to prove causality are time consuming and do not always give clear answers.With this funding we will attempt to optimize the ability to study the causality between VUSs that have been identified in patients and mitochondrial function by using CRISPR/Cas9. With this gene-editing technique, we will repairing the genetic variant in patient fibroblasts restores mitochondrial function. Based on this we can conclude whether the VUS is pathogenic. We postulate that this technique will increase the number of VUSs that can be resolved, improving the diagnostics of mitochondrial disorders and ultimately of other metabolic diseases.
Related news items
Christian Gilissen appointed professor of Genome Bioinformatics22 October 2021
Christian Gilissen has been appointed Professor of Genome Bioinformatics at the Radboudumc / Radboud University as of 1 October 2021.read more
Cell spreading is hard work Bioenergetics of stem cell mechanoresponses in Biomaterials12 November 2020
The study of Bioenergetics of stem cell mechanoresponses, published in Biomaterials is carried out in a collaboration between Werner Koopman, theme Metabolic Diseases, and colleagues from the Radboud University and California Institute of Technology.read more
Khondrion begins study on optimal dosage of new drug10 February 2020
Pharmaceutical company Khondrion, a spin-off from Radboudumc, has taken another important step in the development of its drug sonlicromanol. The first patients have used the drug as part of a phase 2b study, which focuses on determining the optimum dose and efficacy.read more
New mitochondrial DNA maintenance disease uncovered1 October 2019
The group of Hans Spelbrink, theme Mitochondrial diseases, and colleagues, has identified and characterized mutations in the mtDNA maintenance gene SSBP1 in families with optic atrophy and foveopathy. This paper is now online in The Journal of Clinical Investigation.read more
Mitochondrial DNA replication factors in mtRNA metabolism5 February 2019
Hans Spelbrink, theme Mitochondrial diseases, published in Nucleic Acids Research, that two factors in mitochondrial DNA replication, namely the mtDNA helicase Twinkle and the mtDNA single-stranded DNA-binding protein mtSSB, play an important role in mitochondrial RNA metabolism.read more
Tweaking the gearbox of mitochondrial complex I1 November 2018
Alfredo Cabrera-Orefice, Ulrich Brandt and colleagues, theme Mitochondrial Diseases, concluded in Nature Communications that the movement of a critical loop of subunit ND3 located at the ubiquinone-binding pocket of respiratory complex I is required to drive proton pumping.read more