Expanding the molecular and clinical spectrum of POLR3A-related charcot-marie-tooth disease.

BACKGROUND: POLR3A encodes the largest subunit of RNA polymerase III (Pol III), which, together with POLR3B, forms the catalytic core essential for transcribing small non-coding RNAs, including tRNAs and 5 S rRNA. Although biallelic POLR3A variants are well-known causes of hypomyelinating leukodystrophy, a recent study has expanded the phenotypic spectrum to include peripheral neuropathy associated with heterozygous de novo variants. METHODS AND RESULTS: We present an additional case supporting an association between POLR3A dysfunction and Charcot-Marie-Tooth (CMT) disease. The patient was diagnosed with chronic sensorimotor polyneuropathy with conduction velocities in the intermediate range. Whole exome sequencing (WES) identified a heterozygous de novo missense variant, c.2560G > C (p.Gly854Arg), in POLR3A (NM_007055.4). CONCLUSION: This report presents the second description of POLR3A-related CMT and supports the role of RNA polymerase III dysfunction in peripheral neuropathy. Integration of WES and structural analysis showed that the p.Gly854Arg variant affects the bridge helix of POLR3A, a conserved element essential for transcriptional function. Notably, Gly854 appears to be a functional hotspot within the bridge helix-cleft interface, as distinct amino acid substitutions at this position have been independently associated with peripheral neuropathy. These findings expand the molecular and geographical spectrum of POLR3A-related neuropathy.