Abstract
Charcot-Marie-Tooth (CMT) disease comprises up to 80 monogenic inherited neuropathies of the peripheral nervous system (PNS) that collectively result in demyelination and axon degeneration. The majority of CMT disease is primarily either dysmyelinating or demyelinating in which mutations affect the ability of Schwann cells to either assemble or stabilize peripheral nerve myelin. CMT4F is a recessive demyelinating form of the disease caused by mutations in the Periaxin ( PRX) gene . Periaxin (Prx) interacts with Dystrophin Related Protein 2 (Drp2) in an adhesion complex with the laminin receptor Dystroglycan (Dag). In mice the Prx/Drp2/Dag complex assembles adhesive domains at the interface between the abaxonal surface of the myelin sheath and the cytoplasmic surface of the Schwann cell plasma membrane. Assembly of these appositions causes the formation of cytoplasmic channels called Cajal bands beneath the surface of the Schwann cell plasma membrane. Loss of either Periaxin or Drp2 disrupts the appositions and causes CMT in both mouse and man. In a mouse model of CMT4F, complete loss of Periaxin first prevents normal Schwann cell elongation resulting in abnormally short internodal distances which can reduce nerve conduction velocity, and subsequently precipitates demyelination. Distinct functional domains responsible for Periaxin homodimerization and interaction with Drp2 to form the Prx/Drp2/Dag complex have been identified at the N-terminus of Periaxin. However, CMT4F can also be caused by a mutation that results in the truncation of Periaxin at the extreme C-terminus with the loss of 391 amino acids. By modelling this in mice, we show that loss of the C-terminus of Periaxin results in a surprising reduction in Drp2. This would be predicted to cause the observed instability of both appositions and myelin, and contribute significantly to the clinical phenotype in CMT4F.
Highlights
Charcot-Marie-Tooth (CMT) disease is a group of genetically heterogenous neuropathies that comprise the commonest disorders of the peripheral nervous system (PNS)[1]
Periaxin forms a complex with Dystrophin-Related Protein 2 (Drp2) and Dystroglycan (Dag) and this Prx/Dystrophin Related Protein 2 (Drp2)/Dag complex assembles adhesive appositions between the abaxonal surface of PNS myelin and the Schwann cell plasma membrane that are surrounded by cytoplasm-filled Cajal bands[14,15]
Since the N-terminus of Periaxin has been primarily implicated in the assembly of the Prx/Drp2/Dag complex far[15,16,18], we have explored whether loss of the C-terminus might contribute to the formation and/or stabilization of the membrane appositions responsible for the construction of Cajal bands
Summary
Charcot-Marie-Tooth (CMT) disease is a group of genetically heterogenous neuropathies that comprise the commonest disorders of the peripheral nervous system (PNS)[1]. Since most CMT4F nonsense or frame-shift mutations are located in this exon, the corresponding mRNAs that encode premature stop codons are likely to escape nonsense-mediated RNA decay and result in the production of a mutant version of the Periaxin protein[20]. Proof that this is the case has been obtained using sural nerve biopsies from two families harbouring distinct mutations[8,9]. Since the N-terminus of Periaxin has been primarily implicated in the assembly of the Prx/Drp2/Dag complex far[15,16,18], we have explored whether loss of the C-terminus might contribute to the formation and/or stabilization of the membrane appositions responsible for the construction of Cajal bands
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