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  • Review Article
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Disease mechanisms in inherited neuropathies

Nature Reviews Neuroscience volume 4, pages 714–726 (2003)Cite this article

Key Points

  • 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 KIF1Bβ, 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.

Abstract

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.

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Figure 1: The pathological features of HNPP, CMT1A and DSS.
Figure 2: Schematic overview of pathological changes in Charcot–Marie–Tooth disease 1 (CMT1).
Figure 3: Schematic overview of the molecular organization of myelinated axons highlighting the proteins affected in Charcot–Marie–Tooth disease (CMT).
Figure 4: Locations of mutations in the Cx32, P0, PMP22, EGR2 and NEFL proteins.
Figure 5: Relationships between inherited neuropathies and other diseases.

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Acknowledgements

We apologize to our colleagues whose work we could not cite owing to space restrictions. In particular, please consult the Mutation Database for Inherited Peripheral Neuropathies for the original references referring to the different mutations found in hereditary neuropathies. The work in our laboratories is supported by the Swiss National Science Foundation, the National Center of Competence in Research 'Neural Plasticity and Repair' (to U.S.), the Charcot–Marie–Tooth Association, the National Multiple Sclerosis Society and the National Institutes of Health (to S.S.S.).

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Authors and Affiliations

  1. Institute of Cell Biology, Swiss Federal Institute of Technology Zürich, ETH-Hönggerberg, Zürich, CH-8093, Switzerland

    Ueli Suter

  2. The University of Pennsylvania Medical Center, Room 460 Stemmler Hall, 36th Street and Hamilton Walk, Philadelphia, 19104-6077, Pennsylvania, USA

    Steven S. Scherer

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Correspondence to Ueli Suter.

Related links

Related links

DATABASES

LocusLink

EGR2

GARS

GDAP1

GJB1

KIF1B

KIF5A

Limp2/Lgp85

LMNA

MPZ

MTMR2

MTMR13

NCAM

NDRG1

NEFL

p75NTR

PMP22

PRX

RAB7

SOX10

SPTLC1

OMIM

AR-CMT2

CHN

CMT1A

CMT1B

CMT1C

CMT1X

CMT2A

CMT2B

CMT2D

CMT2E

CMT4A

CMT4B1

CMT4B2

CMT4D

CMT4F

dSMAV

DSS

giant axonal neuropathy

HNPP

HSN1

Waardenburg–Shah/Waardenburg type IV syndrome

FURTHER INFORMATION

Charcot–Marie–Tooth Association

Mutation Database for Inherited Peripheral Neuropathies

Muscular Dystrophy Association

The Connexin-deafness homepage

Washington University Neuromuscular homepage

Glossary

ONION BULB

A concentric arrangement of supernumerary Schwann cells around an incompletely remyelinated axon, which is thought to represent repeated cycles of demyelination and remyelination.

HYPOMYELINATED AXON

A remyelinated axon with a myelin sheath that is inappropriately thin for the axonal calibre.

RAFTS

Domains of the plasma membrane enriched in sphingolipids and cholesterol. They incorporate lipid-conjugated proteins and therefore serve to assemble proteins involved in signal transduction.

TETRASPAN

Proteins with four membrane-spanning domains.

INTEGRINS

A large family of transmembrane proteins that act mainly as receptors for extracellular matrix molecules.

DOMINANT-NEGATIVE

A mutant molecule that can form a heteromeric complex with the normal molecule, reducing the activity of the entire complex.

EPITOPE-TAG

The immunological determinant of an antigen that has been fused to a protein of interest for its subsequent localization with specific antibodies.

CALNEXIN

A calcium-binding protein of the endoplasmic reticulum that processes and monitors endoplasmic reticulum proteins, retaining those that are unassembled or incorrectly folded.

CMT2-LIKE PHENOTYPE

A late-onset neuropathy with pronounced axonal loss.

GAP JUNCTION

A junction between two cells consisting of pores that allow passage of molecules (up to 1 kDa).

PLECKSTRIN HOMOLOGY DOMAIN

A sequence of about 100 amino acids that is present in many signalling molecules. Pleckstrin is a protein of unknown function that was originally identified in platelets. It is a principal substrate of protein kinase C.

COILED-COIL DOMAIN

A protein domain that forms a bundle of two or three α-helices. Whereas short coiled-coil domains are involved in protein interactions, long coiled-coil domains, which form long rods, occur in structural or motor proteins.

PDZ-BINDING MOTIF

A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. PDZ-domain-containing proteins bind to the PDZ-binding motifs that are located at the carboxyl termini of proteins or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD95, Discs large, zona occludens 1).

GLAUCOMA

A group of eye diseases characterized by an increase in intraocular pressure which causes pathological changes in the optic disk and typical defects in visual fields.

HAPLOINSUFFICIENCY

Loss of one copy (one allele) of a gene is sufficient to give rise to disease. Haploinsufficiency implies that no dominant-negative effect of the mutated gene product has to be invoked.

AMYOTROPHIC LATERAL SCLEROSIS

A progressive neurological disease that is associated with the degeneration of central and spinal motor neurons. This neuron loss causes muscles to weaken and atrophy.

DYNEIN–DYNACTIN

Dynein is a motor protein complex involved in minus end-directed microtubule transport. Dynactin is a biochemically separable complex that links dynein to target organelles.

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Suter, U., Scherer, S. Disease mechanisms in inherited neuropathies. Nat Rev Neurosci 4, 714–726 (2003). https://doi.org/10.1038/nrn1196

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