A cellular assay to determine the fusion capacity of MFN2 variants linked to Charcot-Marie-Tooth type 2A
Barsa, C.; Perrin, J.; David, C.; Mourier, A.; Rojo, M.
Show abstract
Charcot-Marie-Tooth Disease (CMT) is an inherited peripheral neuropathy with two main forms: demyelinating CMT1 and axonal CMT2. The most frequent subtype of CMT2 (CMT2A) is linked to mutations of MFN2, encoding a membrane-anchored GTP-binding protein essential for mitochondrial outer membrane fusion. The use of Next-Generation Sequencing for genetic analysis has led to the identification of increasing numbers of MFN2 variants, but a majority of them remain variants of unknown significance, depriving patients of a clear diagnosis. In this work, we establish a cellular assay allowing to assess the impact of MFN2 variants linked to CMT2A on the fusion capacity of MFN2. The analysis of 12 MFN2 variants revealed that five abolish fusion, one induces an important reduction and six retain a fusion capacity similar to that of wild-type MFN2. Their analysis with computational variant effect predictors demonstrated a remarkable correlation of our results with predictions based on protein sequence analysis. This work develops novel tools to determine the functional impact of known and novel MFN2 variants and identifies computational tools allowing to predict their possible consequences and pathogenicity.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Imaging-based evaluation of pathogenicity by novel DNM2 variants associated with centronuclear myopathy 95%
- A loss-of-function cysteine mutant in fibulin-3 (EFEMP1) forms aberrant extracellular disulfide-linked homodimers and alters extracellular matrix composition 93%
- Juvenile Mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A 93%
Similar papers in this journal
- Brevican, Neurocan, Tenascin-C and Tenascin-R Act as Important Regulators of the Interplay between Perineuronal Nets, Synaptic Integrity, Inhibitory Interneurons and Otx2 91%
- Human cytomegalovirus vMIA inhibits MAVS oligomerization at peroxisomes in an MFF-dependent manner 91%
- α-Synuclein-112 impairs synaptic vesicle recycling consistent with its enhanced membrane binding properties 91%
Similar papers in this journal
- SMDT1 variants impair EMRE-mediated mitochondrial calcium uptake in patients with muscle involvement 95%
- Similar metabolic pathways are affected in both Congenital Myasthenic Syndrome 22 and Prader Willi Syndrome 91%
- A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders 91%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.