Abstract
Background and aims: Variants in the myelin protein zero coding MPZ gene are responsible for a broad spectrum of peripheral demyelinating and axonal neuropathies, including different types of Charcot-Marie-Tooth diseases, challenging for genotype-phenotype correlation. Methods: Minigene splicing reporter assay was used to unveil the pathogenic mechanism of a novel MPZ(NM_000530.8) c.234 + 1G>C p.(?) heterozygous splice variant. Results: The variant was identified in a 47-year-old female patient presenting with atypical clinical features, including balance disturbance with positive Romberg, absent Achilles tendon reflexes, distal hypoesthesia and bulbar involvement, including dysarthria and dysphagia. Electromyography revealed a sensory-motor neuropathy with moderately reduced nerve conduction velocities. In silico analysis predicted this variant to disrupt the consensual donor splice site located in intron 2 of MPZ. Minigene construction confirmed the functional impact of this variant, revealing exon 2 skipping and the apparition of a premature termination codon. Interpretation: This case expends the genotype-phenotype correlations of MPZ-related Charcot-Marie-Tooth diseases, associating atypical mild phenotype with a rare splice dominant variant, and provides new insights into MPZ haploinsufficiency and pathogenic mechanisms.