A novel out-of-frame mutation in the neurofilament light chain gene ( NEFL) does not result in Charcot-Marie-Tooth disease type 2E

Neurogenetics ◽  
2005 ◽  
Vol 6 (1) ◽  
pp. 49-50 ◽  
Author(s):  
Cinzia Andrigo ◽  
Chiara Boito ◽  
Paola Prandini ◽  
Maria Luisa Mostacciuolo ◽  
Gabriele Siciliano ◽  
...  
Keyword(s):  
Light Chain ◽  
Disease Type ◽  
Chain Gene ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Light Chain Gene ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

Clinical and morphological variability of the E396K mutation in the neurofilament light chain gene in patients with Charcot-Marie- Tooth disease type 2E

2014 ◽  
Vol 33 (09) ◽  
pp. 335-343 ◽  
Author(s):  
Miriam Elbracht ◽  
Jan Senderek ◽  
Ulrike Schara ◽  
Kay Nolte ◽  
Thomas Klopstock ◽  
...  
Keyword(s):  
Light Chain ◽  
Morphological Variability ◽  
Disease Type ◽  
Chain Gene ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Light Chain Gene ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E

2001 ◽  
Vol 49 (2) ◽  
pp. 245-249 ◽  
Author(s):  
Peter De Jonghe ◽  
Irina Mersivanova ◽  
Eva Nelis ◽  
Jurgen Del Favero ◽  
Jean-Jacques Martin ◽  
...  
Keyword(s):  
Light Chain ◽  
Gene Mutations ◽  
Disease Type ◽  
Chain Gene ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Light Chain Gene ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

scholarly journals Neurofilament light chain polypeptide gene mutations in Charcot–Marie–Tooth disease: nonsense mutation probably causes a recessive phenotype

2009 ◽  
Vol 54 (2) ◽  
pp. 94-97 ◽  
Author(s):  
Akiko Abe ◽  
Chikahiko Numakura ◽  
Kayoko Saito ◽  
Hiroyoshi Koide ◽  
Nobuyuki Oka ◽  
...  
Keyword(s):  
Light Chain ◽  
Nonsense Mutation ◽  
Gene Mutations ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Recessive Phenotype ◽  
Tooth Disease

scholarly journals Plasma neurofilament light chain as a potential biomarker in Charcot‐Marie‐Tooth disease

2021 ◽  
Author(s):  
Elina Millere ◽  
Dmitrijs Rots ◽  
Joel Simrén ◽  
Nicholas J. Ashton ◽  
Einars Kupats ◽  
...  
Keyword(s):  
Light Chain ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Potential Biomarker ◽  
Tooth Disease

scholarly journals Allele-specific gene editing rescues pathology in a human model of Charcot-Marie-Tooth disease type 2E

2021 ◽  
Author(s):  
Carissa M. Feliciano ◽  
Kenneth Wu ◽  
Hannah L. Watry ◽  
Chiara B.E. Marley ◽  
Gokul N. Ramadoss ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Light Chain ◽  
Gene Editing ◽  
Human Model ◽  
Specific Gene ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Light Chain Gene ◽  
Charcot Marie Tooth ◽  
Allele Specific

Many neuromuscular disorders are caused by dominant missense mutations that lead to dominant-negative or gain-of-function pathology. This category of disease is challenging to address via drug treatment or gene augmentation therapy because these strategies may not eliminate the effects of the mutant protein or RNA. Thus, effective treatments are severely lacking for these dominant diseases, which often cause severe disability or death. The targeted inactivation of dominant disease alleles by gene editing is a promising approach with the potential to completely remove the cause of pathology with a single treatment. Here, we demonstrate that allele-specific CRISPR gene editing in a human model of axonal Charcot-Marie-Tooth (CMT) disease rescues pathology caused by a dominant missense mutation in the neurofilament light chain gene (NEFL, CMT type 2E). We utilized a rapid and efficient method for generating spinal motor neurons from human induced pluripotent stem cells (iPSCs) derived from a patient with CMT2E. Diseased motor neurons recapitulated known pathologic phenotypes at early time points of differentiation, including aberrant accumulation of neurofilament light chain protein in neuronal cell bodies. We selectively inactivated the disease NEFL allele in patient iPSCs using Cas9 enzymes to introduce a frameshift at the pathogenic N98S mutation. Motor neurons carrying this allele-specific frameshift demonstrated an amelioration of the disease phenotype comparable to that seen in an isogenic control with precise correction of the mutation. Our results validate allele-specific gene editing as a therapeutic approach for CMT2E and as a promising strategy to silence dominant mutations in any gene for which heterozygous loss-of-function is well tolerated. This highlights the potential for gene editing as a therapy for currently untreatable dominant neurologic diseases.

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