Pathomechanisms of mutant proteins in CMT

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Neuromolecular Med. 2006;8(1-2):217-42.

Pathomechanisms of mutant proteins in charcot-marie-tooth disease.

Niemann A, Berger P, Suter U.

Institute of Cell Biology, Department of Biology, Swiss Federal

Institute of Technology, ETH-Honggerberg, CH-8093 Zurich, Switzerland.

We review the putative functions and malfunctions of proteins encoded

by genes mutated in Charcot-Marie-Tooth disease (CMT; inherited motor

and sensory neuropathies) in normal and affected peripheral nerves.

Some proteins implicated in demyelinating CMT, peripheral myelin

protein 22, protein zero (P0), and connexin32 (Cx32/GJB1) are crucial

components of myelin. Periaxin is involved in connecting myelin to

the surrounding basal lamina. Early growth response 2 (EGR2) and

Sox10 are transcriptional regulators of myelin genes. Mutations in

the small integral membrane protein of lysosome/late endosome, the

myotubularin-related protein 2 (MTMR2), and MTMR13/set-binding factor

2 are involved in vesicle and membrane transport and the regulation

of protein degradation.

Pathomechanisms related to alterations of these processes are a

widespread phenomenon in demyelinating neuropathies because mutations

of myelin components may also affect protein biosynthesis, transport,

and/or degradation. Related disease mechanisms are also involved in

axonal neuropathies although there is considerably more functional

heterogeneity.

Some mutations, most notably in P0, GJB1, ganglioside-induced

differentiation-associated protein 1 (GDAP1), neurofilament light

chain (NF-L), and dynamin 2 (DNM2), can result in demyelinating or

axonal neuropathies introducing additional complexity in the

pathogenesis.

Often, this relates to the intimate connection between Schwann cells

and neurons/axons leading to axonal damage even if the mutation-

caused defect is Schwann-cell-autonomous. This mechanism is likely

for P0 and Cx32 mutations and provides the basis for the unifying

hypothesis that also demyelinating neuropathies develop into

functional axonopathies.

In GDAP1 and DNM2 mutants, both Schwann cells and axons/neurons might

be directly affected. NF-L mutants have a primary neuronal defect but

also cause demyelination.

The major challenge ahead lies in determining the individual

contributions by neurons and Schwann cells to the pathology over time

and to delineate the detailed molecular functions of the proteins

associated with CMT in health and disease.