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Discovery of a new pathogenic mechanism in FXTAS disease

Neural nuclei derived from cells of healthy (left) and diseased patients (right). The nucleus in blue and the nuclear envelope in red. Right: In the patients, the FRMpolyG protein (green) interacts with the nuclear envelope and destabilizes it.

Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome.

Sellier C(1), Buijsen RA(2), He F(3), Natla S(4), Jung L(5), Tropel P(5), Gaucherot A(5), Jacobs H(6), Meziane H(6), Vincent A(5), Champy MF(6), Sorg T(6), Pavlovic G(6), Wattenhofer-Donze M(6), Birling MC(6), Oulad-Abdelghani M(5), Eberling P(5), Ruffenach F(5), Joint M(5), Anheim M(7), Martinez-Cerdeno V(8), Tassone F(9), Willemsen R(2), Hukema RK(2), Viville S(10), Martinat C(11), Todd PK(12), Charlet-Berguerand N(13).

Neuron Jan. 18, 2017


Jan. 5, 2017

The team of Nicolas Charlet-Berguerand in collaboration with the Institut clinique de la souris and the teams of Mathieu Anheim (Hôpital de Hautepierre, Strasbourg), Stéphane Viville (Faculty of medicine, Strasbourg) and Cécile Martinat (I-Stem, Paris) highlighted a new pathogenic mechanism implicated in a rare disease: the Fragile X-associated tremor/ataxia syndrome (FXTAS). These results are published in the journal Neuron, on January 5th, 2016.

FXTAS, a syndrome of DNA repetition
The Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative genetic disorder. This rare disease, which occurs in men over the age of 50 years, combines motility disorders (tremor, loss of balance) with cognitive decline. The genetic mutation involved in the FXTAS syndrome is a variant of the one responsible for fragile X syndrome. It consists of an abnormal repetition of three nucleotides (CGG) at the level of the sequence of the FRM1 gene. The number of repetitions has different consequences. Indeed, under 50 repetitions, subjects are healthy and beyond 200, they suffer from fragile X syndrome. The CGG motif is repeated 50 to 200 times in patients with FXTAS syndrome.

 

When repetition translates into protein
While previous studies were focused on a pathogenic mechanism of protein sequestration by excess transcripts, this collaborative study showed that the CGG repeats in the FMR1 gene are actually translated into a new protien, the FMRpolyG, in the absence of an AUG initiation codon. It is indeed an ACG codon, close to the "classical" one, which initiates the translation, but with less efficiency. Before reaching this conclusion, cellular and animal experimentation models were developed by the researchers. Mice with an ACG initiator codon expressed FMRpolyG well and showed clinical signs of the disease, while those lacking this ACG codon (but having the abnormal CGG repeats) showed no symptoms. Beyond this result that challenges previous assumptions, scientists have demonstrated that the FMRpolyG protein interacts with a protein of the nuclear envelope, thus disrupting the cellular architecture of neurons.

 

This work shows that regions of the genome thought to be noncoding can actually be translated into proteins, confirming a phenomenon already observed in previous studies. This process of expression using a codon close to the usual initiation codon highlights a new mechanism of pathogenicity in humans that could possibly explain other diseases.

The results of this study allow us to better understand the molecular causes behind FXTAS in order to establish future therapeutic strategies.

 

This study was funded by the European Research Council (ERC), Inserm and ANR.

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