Identification and Targeted Correction of a Pathogenic PMP22 Deep Intronic Variant.

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Pathogenic variants in the PMP22 gene are associated with hereditary peripheral demyelinating neuropathies.
• These neuropathies include hereditary neuropathy with liability to pressure palsies (HNPP), Charcot-Marie-Tooth disease types 1A and 1E (CMT1A, CMT1E), Roussy-Lévy syndrome, and Dejerine-Sottas disease (DSS).

Purpose of the Study:

• To identify and characterize a novel deep intronic variant in the PMP22 gene.
• To investigate the pathogenicity of the identified variant and its association with specific neuropathy phenotypes.
• To explore potential therapeutic strategies for patients carrying this variant.

Main Methods:

• Genetic analysis of two unrelated Avar families from Dagestan.
• Identification of a deep intronic PMP22 variant (c.179-2809A>G).
• Functional analysis to determine the variant's deleterious effect.
• Assessment of genotype-phenotype correlation in affected individuals.

Main Results:

• A novel deep intronic PMP22 variant, c.179-2809A>G, was identified in nine patients from two Avar families.
• Heterozygous carriers of the variant developed hereditary neuropathy with liability to pressure palsies (HNPP).
• Homozygous carriers presented with a severe Charcot-Marie-Tooth disease type 1A (CMT1A) phenotype, consistent with Dejerine-Sottas disease (DSS).
• Functional analysis confirmed the deleterious impact of the variant.

Conclusions:

• The deep intronic PMP22 variant c.179-2809A>G is a disease-causing mutation in the Avar population.
• This variant should be included in genetic testing for individuals with HNPP traits in this population.
• The study provides a basis for developing personalized antisense therapy for affected individuals.