Abstract
Some mutations affecting dynamin 2 (DNM2) can cause dominantly inherited Charcot–Marie–Tooth (CMT) neuropathy. Here, we describe the analysis of mice carrying the DNM2 K562E mutation which has been associated with dominant-intermediate CMT type B (CMTDIB). Contrary to our expectations, heterozygous DNM2 K562E mutant mice did not develop definitive signs of an axonal or demyelinating neuropathy. Rather, we found a primary myopathy-like phenotype in these mice. A likely interpretation of these results is that the lack of a neuropathy in this mouse model has allowed the unmasking of a primary myopathy due to the DNM2 K562E mutation which might be overshadowed by the neuropathy in humans. Consequently, we hypothesize that a primary myopathy may also contribute to the disease mechanism in some CMTDIB patients. We propose that these findings should be considered in the evaluation of patients, the determination of the underlying disease processes and the development of tailored potential treatment strategies.
Highlights
The peripheral nervous system (PNS) ensures the precise connection between the central nervous system (CNS) and various end organs including skeletal muscles
A likely interpretation of these results is that the lack of a neuropathy in this mouse model has allowed the unmasking of a primary myopathy due to the dynamin 2 (DNM2) K562E mutation which might be overshadowed by the neuropathy in humans
Since CMTDIB patients carrying the DNM2 K562E mutation show behavioural defects that affect both sensory and motor components, we evaluated Dnm2 wt/K562E mice with a collection of behavioural assays for sensory and motor performance
Summary
The peripheral nervous system (PNS) ensures the precise connection between the central nervous system (CNS) and various end organs including skeletal muscles. Peripheral axons of larger diameter with myelin, forming a multilayered compact membranous structure that secures fast saltatory conduction of action potentials in jawed vertebrates [2]. PNS myelination is governed by continuous communication between SCs and neurons/axons, and disturbing either cell in this relationship can be detrimental to peripheral nerve function [5]. Charcot–Marie–Tooth (CMT) disease, called hereditary motor and sensory neuropathies, is a genetically heterogeneous group of disorders caused by mutations that affect the functions of either SCs or axons primarily or both [6,7,8,9]. Normal or mildly reduced NCVs and reduced amplitudes of compound muscle action potentials (CMAPs) denote axonal CMT, coherent with a loss of myelinating large-calibre axons found in nerve biopsies (CMT2). CMT patients typically display distal sensory loss and muscle weakness due to the peripheral nerve defects, followed by secondary muscle wasting that is associated with skeletal deformations including pes cavus, hammer toes and kyphoscoliosis [6,10]
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