Novel Dominant Splicing Variant in MPZ Associated With Unusual Charcot-Marie-Tooth Disease

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Mutations in the myelin protein zero (MPZ) gene cause diverse peripheral neuropathies.
• Genotype-phenotype correlations in MPZ-related disorders are complex and challenging.
• MPZ gene variants lead to demyelinating and axonal neuropathies, including Charcot-Marie-Tooth disease.

Purpose of the Study:

• To investigate the pathogenic mechanism of a novel MPZ gene splice variant.
• To expand genotype-phenotype correlations for MPZ-related Charcot-Marie-Tooth diseases.
• To provide insights into MPZ haploinsufficiency and disease mechanisms.

Main Methods:

• Identified a novel MPZ splice variant (c.234+1G>C) in a patient with atypical neuropathy.
• Utilized in silico analysis to predict splice site disruption.
• Employed a minigene splicing reporter assay to confirm the variant's functional impact.

Main Results:

• The MPZ variant disrupted the donor splice site in intron 2, causing exon 2 skipping.
• This resulted in a premature termination codon, indicating a pathogenic mechanism.
• The patient presented with mild, atypical symptoms including bulbar involvement and sensory-motor neuropathy.

Conclusions:

• This study associates a rare splice-dominant MPZ variant with an atypical, mild Charcot-Marie-Tooth disease phenotype.
• The findings enhance understanding of genotype-phenotype correlations in MPZ-related neuropathies.
• New insights into MPZ haploinsufficiency and its pathogenic mechanisms were provided.