PRX

Periaxin (PRX) is a PDZ-domain-containing scaffolding protein expressed as two major isoforms—L-PRX (1461 aa) and S-PRX (147 aa)—that differ by intron 6 retention, and functions in myelin stability, endothelial barrier integrity, and lens development. Loss-of-function mutations affecting L-PRX cause autosomal recessive demyelinating Charcot-Marie-Tooth disease type 4F (CMT4F), characterized by peripheral nerve demyelination with prominent sensory abnormalities (PMID:21741241, PMID:16534116). In human cerebral endothelial cells, PRX localizes predominantly to the nucleus, strengthens barrier function, and suppresses Type I interferon response genes through a mechanism that requires only its PDZ domain (PMID:29968755). Dominant splicing variants in the intron 6 region that replace L-PRX with S-PRX or produce aberrant L-PRX cause congenital cataract through a likely gain-of-function or dominant-negative mechanism disrupting lens cortex organization (PMID:41230902).

1. 2011 Medium

   Establishing that PRX loss-of-function causes peripheral demyelination resolved the gene's essential role in myelin maintenance and defined CMT4F as a PRX-linked neuropathy.

   Evidence Genetic analysis and sequencing of PRX in consanguineous families with demyelinating neuropathy

   PMID:16534116 PMID:18504680 PMID:21741241 PMID:25628743

   Open questions at the time

   • Molecular mechanism by which L-PRX stabilizes peripheral myelin is undefined
   • Whether S-PRX contributes to peripheral nerve function is unknown
   • No structural model of full-length L-PRX exists
2. 2018 Medium

   Demonstrating that the PDZ domain alone is necessary and sufficient for endothelial barrier enhancement identified the minimal functional unit and revealed a previously unknown role for PRX in vascular biology and innate immune suppression.

   Evidence Overexpression of full-length PRX and S-PRX (PDZ-only) in mouse endothelial cells with transendothelial electrical resistance, permeability assays, and transcriptome profiling

   PMID:29968755

   Open questions at the time

   • Endothelial barrier function was tested only by heterologous overexpression; loss-of-function in human cerebral endothelium not examined
   • Direct transcriptional targets mediating Type I interferon suppression are unidentified
   • Nuclear binding partners of PRX in endothelial cells are unknown
3. 2025 Medium

   RNA-seq-validated splicing variants showed that dominant shifts in isoform balance—replacement of L-PRX by S-PRX or production of aberrant L-PRX—cause congenital cataract, establishing isoform-specific pathomechanisms distinct from the recessive neuropathy.

   Evidence Exome/genome sequencing and RNA sequencing of multiple families with congenital cataract confirming aberrant intron 6 splicing

   PMID:41230902

   Open questions at the time

   • Whether the cataract mechanism is gain-of-function versus dominant-negative has not been distinguished experimentally
   • L-PRX interaction partners at lens adherens junctions are uncharacterized
   • Animal models recapitulating the dominant cataract phenotype are lacking

• The biochemical activities of L-PRX beyond scaffolding—its direct binding partners in myelin, endothelium, and lens, the structural basis of PDZ-domain-mediated barrier function, and the mechanism linking isoform imbalance to dominant cataract—remain open questions.
• No reconstituted biochemical assay for PRX activity exists
• Structural basis for PDZ domain function in barrier integrity is unknown
• Comprehensive interactome in disease-relevant tissues has not been determined