How do GGC repeat expansions located in a “non-coding” 5′UTR region lead to a myopathy?
1 : Institut de Génétique et de Biologie Moléculaire et Cellulaire
université de Strasbourg, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale : U964, Centre National de la Recherche Scientifique : UMR7104, université de Strasbourg : UMR7104, Institut National de la Santé et de la Recherche Médicale : U1258
Oculo-Pharyngo-Distal Myopathy type 1 (OPDM1, OMIM #164310) is a rare adult-onset
genetic neuromuscular disorder characterized by progressive weakness and atrophy of
facial, pharyngeal, and distal limbs skeletal muscles. At the histopathological level,
OPDM muscle fibers are characterized by the presence of typical intranuclear inclusions,
which are p62-positive, but of unknown origin. Thanks to progress in whole genome and
long read sequencing, the genetic cause of OPDM1 was recently identified as an abnormal
expansion of 50 to 200 GGC repeats in the 5′ untranslated region (5′UTR) of the LRP12
gene.
Here, we found that these GGC repeats lie within a previously unrecognized small open
reading frame (sORF), resulting in their translation into a novel polyGlycine-containing
protein. Mass-spectrometry analysis indicates that translation initiation occurs at two near
cognate CTG and GTG start codons located upstream of the GGC repeats. Near-cognate
start codons are codons differing from the cognate AUG start codon by one nucleotide, but
that can nonetheless initiate translation through mispairing with the initiator methionine
tRNA. Imporatntly, expression of this novel polyGlycine protein forms p62-positive
intranuclear inclusions in muscle cells, thus, recapitulating a key feature of this disease.
We are now in the process of determining the toxicity of this polyGlycine protein in cell
culture, and future studies will focus on developing antibodies to test its expression in
patient tissues, as well as developing an animal model for this disease.
Overall, these findings suggest that OPDM1 is as a repeat expansion disorder caused by
expression of a novel and potentially toxic polyGlycine protein.
| Type : | : | Choisir oral ou poster |
| Thématiques | : | Poster |
| Mots-Clés | : | OPDM1 ; LRP12 ; GGC repeat expansion ; 5′UTR ; near ; cognate start codon ; polyGlycine protein ; p62 ; positive intranuclear inclusions ; repeat expansion disorder ; skeletal muscle weakness ; translational initiation |
| PDF version | : |  PDF version |
