PRX – Charcot-Marie-Tooth Disease

The association between PRX and Charcot-Marie-Tooth disease is supported by robust genetic and functional evidence. Studies have identified loss‑of‑function mutations in PRX associated with a demyelinating neuropathy phenotype. The genetic findings indicate an autosomal recessive inheritance pattern with several novel truncating mutations found in unrelated probands (PMID:12112076). This evidence provides a strong basis for linking PRX gene disruption to neuropathic outcomes.

Detailed genetic analyses have revealed multiple PRX variants, including the representative variant c.1864C>T (p.Gln622Ter), which is consistent with a loss‑of‑function mechanism. These variants were identified in at least two distinct families, with segregating variants observed among affected siblings and relatives, further solidifying the genetic association (PMID:12112076). The variant spectrum is characterized by truncating mutations that disrupt the formation of the functional periaxin protein.

Segregation studies in the reported families show that affected individuals consistently carry deleterious PRX mutations, further supporting the role of PRX in disease pathogenesis. The clustering of truncating mutations in patients with demyelinating phenotypes demonstrates clear genotype‑phenotype concordance. This pattern of inheritance has important implications for genetic counseling and risk assessment in families with Charcot-Marie-Tooth disease (PMID:12112076).

Functional studies have elucidated the pathogenic mechanism by demonstrating that alterations in PRX lead to impaired protein interactions. Experiments using immunofluorescence, co‑immunoprecipitation, and GST pull‑down assays have shown that the interaction between L‑ and S‑periaxin isoforms is critical for Schwann cell function (PMID:26467811). The disruption of this interaction likely contributes to abnormal myelination and the development of a peripheral neuropathy phenotype.

Integration of genetic and functional evidence provides a coherent narrative: PRX truncating mutations cause a loss‑of‑function that disrupts critical protein interactions in Schwann cells, leading to demyelination and subsequent manifestation of Charcot-Marie-Tooth disease. The observed clinical spectrum, ranging from classic demyelinating patterns to severe sensory impairment, emphasizes the heterogeneity and clinical significance of PRX mutations. This integrated evidence supports the utility of genetic testing for PRX in the diagnostic workup of patients with inherited neuropathies.

Key take‑home: PRX genetic testing is a valuable tool in diagnosing demyelinating Charcot-Marie-Tooth disease, informing patient management and facilitating targeted therapeutic strategies.

References

• Annals of Neurology • 2002 • Periaxin mutations cause a broad spectrum of demyelinating neuropathies PMID:12112076
• Neuroscience Letters • 2015 • L‑periaxin interacts with S‑periaxin through its PDZ domain PMID:26467811

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