Agnès Rötig

Genetics of mitochondrial diseases

Publish at 18.11.2019


Agnès Rôtig


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Genetics of mitochondrial diseases


Mitochondrial diseases are characterized by a huge clinical and genetic heterogeneity and the mitochondrial and nuclear disease causing genes have been identified in only 20% of cases. Moreover, there is almost no therapy for these devastating diseases.

Therefore our objectives are:

  1. to identify new nuclear genes responsible for mitochondrial dysfunction in human for a better understanding of its heterogeneity
  2. to improve our understanding on the replication of mitochondrial DNA during embryo-feral development with the aim to propose prenatal procedures for mtDNA disorders
  3. to test on patients fibroblasts drugs previously identified in yeast to restore deficient mitochondrial functions.

Gene identification by next generation sequencing

The number of disease-causing mutations in mitochondrial diseases is constantly growing but it should be borne in mind that no mutation has been identified in 70% of the patients. The clinical and genetic heterogeneity of these diseases as well as the large number of candidate genes (1000-2000) make the identification of these genes more and more difficult. Indeed, we are now facing a large number of sporadic cases. Therefore, next generation sequencing has been proved to be the best approach to identify new disease genes. We have already performed and will keep on doing exome sequencing for our patients. Nevertheless, our experience has taught us that exome sequencing is particularly successful i) when performed on two or more affected sibs or on clinically homogenous patients and ii) when guided by a specific biochemical phenotype. Therefore, we shall now combine various biochemical approaches (RC assembly, mitochondrial translation) with the aim of better characterizing the abnormal mitochondrial function and/or defining the best candidate genes. Depending on the function of the mutant genes, various approaches will be developed with the aim of validating the pathogenicity of the mutations.

Mitochondrial DNA replication during embryo-fetal development

Eukaryotic cells contain a large number of copies of maternally inherited mtDNA. Very few data are available with respect to mtDNA replication during human oogenesis and embryogenesis, both in wild-type individuals and carriers of mtDNA mutations. Most of the data were obtained in animals and are sometimes contradictory. The lack of data on mtDNA replication during embryo-fetal development hampers to propose fully reliable pregestational and prenatal diagnosis to couples at risk to transmit mtDNA mutation. Our project aims at studying when and how normal and mutant mtDNA replicates throughout embryofetal development in human. In order to get an insight into these questions, we have collected a large number of human samples from control and mutant adult females (gametes and somatic cells), control and mutated embryos, fetuses and placentas. Using these samples, we shall assess the mtDNA copy number and mutation rate, the mtDNA replication, and the expression level of both mitochondrial genes and nuclear genes involved in replication and transcription of mtDNA, at the single cell level.

Neurodegeneration with brain iron accumulation (NBIA)

NBIA encompasses a group of rare neurodegenerative disorders transmitted as an autosomal recessive trait1. We are interested by NBIA because (i) mitochondrial dysfunction is often suspected as a differential diagnosis of NBIA, (ii) it is related to Friedreich ataxia due to mutations of frataxin, a mitochondrial protein involved in iron metabolism and (iii) our local recruitment via Neuroradiology Unit of our Hospital. By exome sequencing we have identified a novel NBIA gene. This gene is involved in endocytosis and further work is underway to determine its involvement in iron metabolism.

Therapeutic approach of mitochondrial diseases

No efficient treatment of mitochondrial diseases is presently available. The use of human cells for testing a large number of drugs is relatively difficult as the only available cells are patient’s fibroblasts that grow relatively slowly and as the study of mitochondrial functions require a relatively high amount of cells and is time consuming. We have initiated a consortium project aiming at using simple organisms such as Saccharomyces cerevisiae and Caenorhabditis elegans as tools for the first screen of drug libraries capable to modulate and/or restore deficient mitochondrial functions. This consortium includes four groups that are experts of mitochondrial functions in yeast and worm, chemists, and two groups involved in human genetics mainly involved in adult patients and our group in Necker hospital involved in pediatric patients. Yeasts or worms carrying nuclear or mitochondrial mutations corresponding to human disease mutations have been used for rapid screening of drug libraries that allowed to identify a small number of possible therapeutic molecules that will be tested on patient’s fibroblasts.

Abstract 09

Research: a scientific adventure

Our goal: to better understand genetic diseases to better treat them.