In this study, we show that activation of the chaperone pathway in fibroblasts from PMP22 duplication-associated Charcot-Marie-Tooth disease type 1A patient with an FDA-approved small molecule increases HSP70 expression and attenuates proteasome dysfunction.
Mutations of the peripheral myelin protein-22 (PMP22) gene are the most common cause of inherited disease of the peripheral nervous system (PNS), with its deletion resulting in hereditary neuropathy with liability to pressure palsies (HNPP), and its duplication inducing Charcot-Marie-Tooth 1A (CMT1A) disease.
Molecular and clinical studies of copy number variants involving chromosome 17 began with locus-specific studies of Charcot-Marie-Tooth disease type 1A (CMT1A, OMIM #118220) and hereditary neuropathy with liability to pressure palsies (HNPP, OMIM #162500), which laid the foundation for the paradigm of duplication/deletion and gene-dosage for our understanding of genomic disorders.
Hereditary neuropathy with liability to pressure palsies (HNPP), Charcot-Marie Tooth disease type 1A (CMT1A), Dejerine-Sottas syndrome, and congenital hypomyelinating neuropathy are all associated with defects in PMP22 gene.
The duplication of PMP22 is the most common cause of the demyelinating form of the autosomal dominant Charcot-Marie-Tooth neuropathy (CMT1A); rarer missense mutations of PMP22 also cause CMT1A or severe dehypomyelinating neuropathies of infancy grouped under the heading of Dejerine-Sottas syndrome (DSS).
The HNPP (hereditary neuropathy with liability to pressure palsies) deletion and CMT1A (Charcot-Marie-Tooth disease type 1A) duplication are the reciprocal products of homologous recombination events between misaligned flanking CMT1A-REP repeats on chromosome 17p11.2-p12.
Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary demyelinating neuropathy linked with duplication of the peripheral myelin protein 22 (PMP22) gene.
Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by 1.5-fold increased dosage of the PMP22; however, onset age and severity vary considerably among patients.
A son heterozygous for the PMP22 point mutation had no signs of neuropathy, while two others heterozygous for the deletion had HNPP, suggesting that point mutations in PMP22 can result in dominant and recessive alleles contributing to CMT1A.
Charcot-Marie-Tooth disease type 1A (CMT 1A) is an autosomal dominant demyelinating polyneuropathy associated with a 1.5-Mb duplication of the p11.2-p12 region of chromosome 17, including the peripheral myelin protein-22 (PMP-22) gene (CMT 1A duplication).
Perhaps the most extensively characterized genomic region prone to rearrangement is 17p12, which is associated with the peripheral neuropathies, hereditary neuropathy with liability to pressure palsies (HNPP) and Charcot-Marie-Tooth disease type 1A (CMT1A;ref.2).
Genomic rearrangements involving the peripheral myelin protein gene (PMP22) in human chromosome 17p12 are associated with neuropathy: duplications cause Charcot-Marie-Tooth disease type 1A (CMT1A), whereas deletions lead to hereditary neuropathy with liability to pressure palsies (HNPP).