DEFINITION
Charcot-Marie-Tooth disease type 1A is caused by duplication of the gene encoding peripheral myelin protein-22 (PMP22; 601097) on chromosome 17p12.
PMP22 localization
Charcot-Marie-Tooth CMT1A
Charcot-Marie-Tooth
Genes involved in CMT
Pathomechanisms of Mutant Proteins in Charcot-Marie-Tooth Disease, 2006
EPIDEMIOLOGY
age, sex, seasonality, etc
SYMPTOMS
DIAGNOSIS
histopathology
radiology
NMR
laboratory tests
PATHOGENESIS
Duplication of PMP22 metabolic effects:
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PMP22 Is Critical for Actin-Mediated Cellular Functions and for Establishing Lipid Rafts, 2014
Haploinsufficiency of peripheral myelin protein 22 (PMP22) causes hereditary neuropathy with liability to pressure palsies, a peripheral nerve lesion induced by minimal trauma or compression. As PMP22 is localized to cholesterol-enriched membrane domains that are closely linked with the underlying actin network, we asked whether the myelin instability associated with PMP22 deficiency could be mediated by the involvement of the protein in actin-dependent cellular functions and/or lipid raft integrity. In peripheral nerves and cells
from mice with PMP22 deletion, we assessed the organization of filamentous actin (F-actin), and actin-dependent cellular functions.
Using in vitro models, we discovered that, in the absence of PMP22, the migration and adhesion capacity of Schwann cells and fibroblasts are similarly impaired. Furthermore, PMP22-deficient Schwann cells produce shortened myelin internodes, and display compressed axial cell length and collapsed lamellipodia. During early postnatal development, F-actin-enriched Schmidt-Lanterman incisures do not form properly in nerves from PMP22 / mice, and the expression and localization of molecules associated with uncompacted myelin domains and lipid rafts, including flotillin-1, cholesterol, and GM1 ganglioside, are altered. In addition, we identified changes in the levels and distribution of cholesterol and ApoE when PMP22 is absent. Significantly, cholesterol supplementation of the culture medium corrects the elongation and migration deficits of PMP22 / Schwann cells, suggesting that the observed functional impairments are directly linked with cholesterol deficiency of the plasma membrane. Our findings support a novel role for PMP22inthe linkage of the actin cytoskeleton with the plasma membrane, likely through regulating the cholesterol content of lipid rafts.
PATIENT RISK FACTORS
Vascular
Genetic
Acquired
Hormonal
Genetic
Acquired
TISSUE SPECIFIC RISK FACTORS
anatomical (due to its structure)
vascular (due to the local circulation)
physiopathological (due to tissue function and activity)
COMPLICATIONS
THERAPY
Charcot-Marie-Tooth disease and glutathione
