Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 7-Day Trial for You or Your Team.

Learn More →

Disease mechanisms in inherited neuropathies

Disease mechanisms in inherited neuropathies 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Reviews Neuroscience Springer Journals

Disease mechanisms in inherited neuropathies

Download PDF
13 pages

Loading next page...
 
/lp/springer-journals/disease-mechanisms-in-inherited-neuropathies-hoVMKaMxMK

References (165)

Publisher
Springer Journals
Copyright
Copyright © 2003 by Nature Publishing Group
Subject
Biomedicine; Biomedicine, general; Neurosciences; Behavioral Sciences; Biological Techniques; Neurobiology; Animal Genetics and Genomics
ISSN
1471-003X
eISSN
1471-0048
DOI
10.1038/nrn1196
Publisher site
See Article on Publisher Site

Abstract

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.

Journal

Nature Reviews Neuroscience – Springer Journals

Published: Sep 1, 2003

There are no references for this article.