Periaxin mutation in Japanese patients with Charcot-Marie-Tooth disease

Abstract

Periaxin (PRX) plays an important role in the myelination of the peripheral nerve and consequently in the pathogenesis of Charcot-Marie-Tooth disease (CMT). To date, nine nonsense or frameshift PRX mutations have been reported in eight families with CMT. The patients with PRX mutations appeared to show characteristic clinical features with early onset but slow or no progression, a common result of mutations that lead to missing a C-terminal acidic domain. Here, we report a Japanese CMT patient with these characteristic clinical features, who was a compound heterozygote for PRX R1070X and L132FsX153 mutations. We previously reported that three Japanese isolated families also had the homozygous R1070X mutation. To examine the potential founder effect of the R1070X mutation in the Japanese population, we performed haplotype analysis and found that each R1070X allele lay on a different haplotype background in these four families. Therefore, the high frequency of the R1070X mutation among the Japanese population is not likely the consequence of a founder effect, but probably a result of a mutation hot spot.

Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes

“…Because myelin is necessary for the conduction of high-frequency and high-velocity nerve impulses by saltatory conduction, its defects lead to severe neuropathy. In humans, nonsense mutations in periaxin cause an autosomal recessive form of CMT4F (Dejerin-Sottas disease), which is one of the severe hereditary motor and sensory neuropathies [31,32]. It was also reported that periaxin-knockout mice exhibit peripheral demyelination, mechanical allodynia, and thermal hyperalgesia [33].…”

Direct binding of the flexible C-terminal segment of periaxin to β4 integrin suggests a molecular basis for CMT4F

“…In order to identify putative protein ligands for the C-terminal segment of L-PRX, which is missing in the presence of the CMT4F R1070X mutation (24,28), we carried out a yeast 2-hybrid screen of a rat sciatic nerve cDNA library with the C-terminal segment, missing upon the R1070X mutation, as bait. As a result, we obtained three separate clones containing the β4-FNIII-3 domain (Figure 1A).…”

“…Proteomics analyses were carried out exactly as described (24), comparing the PRX-bound proteomes of PRX -/- mice carrying a transgene for either wild-type PRX (PrxTg/PRX -/- ) or PRX with a C-terminal truncation mutation (mouse L-PRX truncated at residue 1016; ΔCPrxTg/PRX -/- ) corresponding to human CMT4F R1070X (28,29). Proteins from mouse nerve lysates were crosslinked followed by immunoprecipitation with a PRX antibody, and then subjected to mass spectrometry (MS) analyses.…”

A 71‐nucleotide deletion in the periaxin gene in a Romani patient with early‐onset slowly progressive demyelinating CMT

“…So far, 10 different frameshift or non‐sense PRX mutations were reported to cause autosomal recessive (AR) early‐onset demyelinating neuropathy [6]. It develops further in the course either as severe Dejerine–Sottas syndrome [7,8] or demyelinating CMT with slow or no progression [8–10].…”

“…The protein has four characteristic domains: PDZ, nuclear localization signal, repeat and acidic domains [13–15]. Loss of the acidic domain is shared by all pathogenic mutations in the gene reported so far and presumably plays a role in the disease pathogenesis [7–10,16].…”