A collaboration between the Medical Research Council (MRC) Centre for Neuromuscular Diseases at UCL Institute of Neurology, the Medical University Vienna and the John P. Hussman Institute for Human Genetics, University of Miami has identified abnormal protein aggregation secondary to mutations in the Neurofilament heavy chain as a cause of autosomal Dominant Charcot Marie Tooth disease type 2 (CMT2).

CMT is the commonest inherited neuromuscular disorders affecting 1 in 2,500 patients. Although most of the causative genes have been found for CMT1 (demyelinating CMT) only 50% of the causative genes for CMT2 (axonal CMT) have been identified to date.

In the current study, whole exome sequencing in a family with CMT2 identified by Professor Mary Reilly revealed a mutation in the NEFH gene as the cause of the disease. Neurofilaments are exclusively expressed in neurons and are major components of the cytoskeleton responsible for regulating axonal diameter and growth. The current study showed that the neuropathy is due to abnormal NEFH protein aggregation. This was shown to be secondary to a mutation which caused failure of normal reading frame termination resulting in translation of a normally untranslated amyloidogenic region prone to aggregation.

This study adds CMT to the growing list of neuromuscular and neurodegenerative diseases caused by abnormal protein aggregation. Studying the mechanisms underlying these disorders will hopefully lead to the identification of tractable targets for drug development.

 “Identifying abnormal aggregation of NEFH as a cause of CMT2 is an important step forward in understanding the pathogenesis of the inherited axonal neuropathies. Neurofilaments are major axonal cytoskeleton proteins and it is of considerable interest that abnormal protein aggregration is the underlying mechanism as has been found in other neuromuscular diseases and other neurodegenerative diseases such as Alzheimer’s disease. This collaborative study demonstrates the power of the in depth study of families with rare genetic diseases to help our understanding of more widely applicable disease mechanisms.”  Co-senior author of the paper, Professor Mary Reilly, MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology.
“Protein aggregation disorders are emerging as an important mechanism for an increasing number of neuromuscular diseases e.g. motor neurone diseases and inclusion body myositis. This interdisciplinary transatlantic collaboration now shows that axonal CMT can also be a protein aggregation disorder. Proteostasis is emerging as an important target for neuromuscular diseases as well as for neurodegenerative diseases and is a major research theme for many teams at the UCL Institute of Neurology.” Professor Michael Hanna, Director of the UCL Institute of Neurology.

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