Disease Mechanisms in Inherited Neuropathies

[Guest guest]

September 2003 Vol 4 No 9

REVIEW

Nature Reviews Neuroscience 4, 714 -726 (2003); doi:10.1038/nrn1196

DISEASE MECHANISMS IN INHERITED NEUROPATHIES (mentions CMT 1A and 1B)

Ueli Suter & S. Scherer

Preface

Inherited neuropathies are caused by dominant or recessive mutations in

genes that are expressed by neurons and/or Schwann cells. In

demyelinating neuropathies, the deleterious effects originate primarily

in myelinating Schwann cells. In axonal neuropathies, neurons (axons)

are initially affected. In demyelinating neuropathies, the axonal

cytoskeleton is altered and axonal transport is disrupted. In some

axonal neuropathies, genes that are directly involved in axonal

transport are mutated. So, a common consequence of inherited

neuropathies is disruption of the ability of neurons to transport cargo

efficiently along the entire length of their axons. These findings

correlate with the observations that axonal atrophy and/or loss are

primarily responsible for the clinical disability in hereditary

neuropathies.

Summary

Hereditary neuropathies are genetically heterogeneous and affect neurons

and/or Schwann cells. Mutations in several different genes can lead to

the same disease phenotype. Conversely, different mutations affecting

the same gene can lead to different disease phenotypes. Deletion or

duplication of a 1.4 megabase intrachromosomal region on

chromosome 17 containing the PMP22 gene causes hereditary neuropathy

with liability to pressure palsies or demyelinating Charcot–Marie–Tooth

disease (CMT1A), respectively, the most common forms of dominantly

inherited demyelinating neuropathy. The deleterious effects of PMP22

gene dosage correlate with the relative amounts of PMP22 protein in

compact myelin.

Most dominant PMP22 missense mutations that cause disease encode mutant

proteins that are retained in the endoplasmic reticulum and/or

intermediate compartment. These mutants act by gain of function, and

some undergo abnormally prolonged interactions with calnexin, a

glycoprotein-specific chaperone.

Of the MPZ (P0) mutations that cause CMT1B, many affect adhesion of

myelin lamellae, leading to unstable myelin. Other mutations probably

have other kinds of gain-of-function effects. Most GJB1 (Cx32) mutations

cause a loss of function, probably by disrupting gap junction-mediated

diffusion across the myelin sheath. Transcription factors regulating the

expression of myelin genes, including early growth response 2 (EGR2) and

SOX10, are mutated in demyelinating forms of hereditary neuropathies.

Demyelination disrupts axon–Schwann cell interactions and has numerous

effects on axons (for example, reduction of calibre, reorganization of

ion channels, alteration of neurofilament density and phosphorylation)

leading to deficiencies in axonal transport. Altered axonal transport

can lead to distally accentuated axonal loss, which is responsible for

the clinical disability of patients with inherited demyelinating

neuropathies. Mutations affecting components of the axonal cytoskeleton,

including

neurofilaments and the molecular motor KIF1B, are mutated in axonal

forms of CMT. Together with the findings that KIF5A mutations cause

inherited spastic paraplegia, and a mutation of dynactin causes motor

neuron disease, these data indicate that axonal transport is an

important contributor to axonal atrophy and length-dependent axonal loss

in these related disorders.