A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease

Abstract

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies characterized by chronic distal weakness with progressive muscular atrophy and sensory loss in the distal extremities. Inheritance can be autosomal dominant, X-linked or autosomal recessive (ARCMT). Recently, a locus responsible for a demyelinating form of ARCMT disease, named CMT4F, has been mapped on 19q13 in a large consanguineous Lebanese family. L- and S-periaxin are proteins of myelinating Schwann cells and homozygous periaxin-null mice display extensive demyelination of myelinated fibers in the peripheral nervous system, which suggests that the periaxin gene is a good candidate gene for an ARCMT disease. The human gene encoding the periaxins (PRX) was mapped to 19q13, in the CMT4F candidate interval. After characterizing the human PRX gene, we identified a nonsense R196X mutation in the Lebanese family which cosegregated with CMT. Histopathological and immunohistochemical analysis of a sural nerve biopsy of one patient revealed common features with the mouse mutant and the absence of L-periaxin from the myelin sheath. These data confirm the importance of the periaxin proteins to normal Schwann cell function and substantiate the utility of the periaxin-null mouse as a model of ARCMT disease.

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

“…Similar clinical manifestations are observed in patients carrying mutations in different genes, while variable presentations are present even in patients with an identical mutation in the same gene. Recently, there have been several reports that the periaxin (PRX) mutations were detected in the patients showing early onset of symptoms, but with slow or no progression (Boerkoel et al 2001;Guilbot et al 2001;Takashima et al 2002;Kijima et al 2004). We found heterozygous R1070X and L132fsX153 compound mutations of PRX in another patient showing early onset but no progressive clinical symptoms.…”

“…L-periaxin has four characteristic domains: PDZ, NLS, repeat and acidic domains (Gillespie et al 1994;Sherman and Brophy 2000;Sherman et al 2001). To date, nine pedigrees, carrying ten nonsense or frameshift mutations of PRX, have been reported (Boerkoel et al 2001;Guilbot et al 2001;Takashima et al 2002;Kijima et al 2004). It is interesting to note that all nine mutations are predicted to produce mutant proteins that lack an acidic domain.…”

Antibodies to L‐periaxin in sera of patients with peripheral neuropathy produce experimental sensory nerve conduction deficits

“…Mice that lack a functional periaxin protein myelinate peripheral nerve axons normally but develop a severe demyelinating neuropathy (Gillespie et al 2000). Mutations in the periaxin gene have been recently identified in a small number of patients with inherited demyelinating forms of Dejerine-Sottas or Charcot-Marie-Tooth peripheral neuropathies (Boerkoel et al 2001;Guilbot et al 2001). Experimental demyelination produced by intraneural injection of sera containing anti-L-periaxin antibodies, as shown in this study, is consistent with a role of this protein in the maintenance of the mature myelin sheath.…”

The use of whole-exome sequencing to disentangle complex phenotypes

“…The mutation lies within the PRX domain of the protein and has previously been described in the literature (chr19.hg19:g.40901051; rs104894708) to cause Charcot-Marie-Tooth disease type 4 F (CMT4F) and Dejerine-Sottas disease. [6][7][8][9][10][11] Sanger sequencing confirmed the PRX mutation and showed it segregated with disease in the family in a recessive manner (Figure 1). …”