Nicolas Vignier is a technician that has joined Gisèle Bonne’s research group within UMRS 974 at the Institute of Myology. Thanks to his work in Lucie Carrier’s group in collaboration with research groups from the CEA and Hamburg, he has just published an article showing the involvement of two regulatory systems designed to lower the rate of protein mutated in a cardiomyopathy in the journal Circulation Research*.
Can you describe how your work sheds light on the development of cardiomyopathy?
The main interest of this paper is the identification of molecular mechanisms underlying the pathology. The mouse model that we developed carries a point mutation in the MYBPC3 gene and enabled the involvement of two regulatory systems of missense and/or nonsense mutations. The NMD system (“Nonsense-Mediated RNA Decay”) that supports messenger RNAs that carry a premature stop codon to degrade them and the UPS system (“Ubiquitin-Proteasome System”), which recognizes the mutant proteins and leads to their degradation. These systems have been described in other diseases but this is the first time that they have been described in a cardiac pathology of genetic origin.
What put you on the right track?
Two physiopathological hypotheses exist that are involved in the development of this pathology. The first is the polypeptide poison, where the product of a gene will be toxic to the cell. The second hypothesis that we prefer, is haploinsufficiency where only 1 of the 2 alleles is expressed, resulting in a decrease of the gene products and disease onset. The significant decrease in quantity of MYBPC3 messenger RNA and synthesized protein in homozygous or heterozygous mice confirmed our hypothesis. We then sought to explain this decrease.
Will this discovery lead to new perspectives for this type of pathology?
When attempting to identify the molecular mechanisms involved in diseases, the importance lies in identifying new therapeutic targets. In our case, it is still early, but one could imagine surmounting a haploinsufficiency by inhibiting the mechanism that created it, either NMD or UPS.
In the article, you talk about “unexpected complexity of the expression of a point mutation in the whole animal”. Can you explain?
We were surprised to find that in this mouse model, we made a point mutation in the last nucleotide of an exon and were expecting to have only one type of mutant at the messenger RNA level, but we obtained three! We identified a mRNA bearing the point mutation that leads to the synthesis of a mutant protein (missense mutation), an mRNA carrying a premature stop codon, which potentially leads to a truncated protein (exon skipping, frameshift, nonsense mutation) and a mRNA bearing a deletion/insertion with restoration of the reading frame that gives a second missense mutant protein. Thus three different types of mRNA were synthesized from a single mutation. That was completely unexpected! And it’s thanks to this that we could highlight the two regulatory mechanisms.
Interview by Anne Berthomier, translation by Racquel N. Cooper
* Vignier N, Schlossarek S, Fraysse B, Mearini G, Kramer E, Pointu H, Mougenot N, Guiard J, Reimer R, Hohenberg H, Schwartz K, Vernet M, Eschenhagen T, Carrier L:
Nonsense-Mediated mRNA Decay and Ubiquitin-Proteasome System Regulate Cardiac Myosin-Binding Protein C Mutant Levels in Cardiomyopathic Mice.
Circ Res, 2009 Jul 31;105(3):239-48. Epub 2009 Jul 9.