Monoallelic POLR3A Variants Cause Early-Onset Peripheral Neuropathy

Heterozygous *POLR3A* variants impair Pol III function, depleting tRNA pools and causing peripheral neurodegeneration

Heterozygous variants in POLR3A, encoding a subunit of the RNA Polymerase III (Pol III) complex, were identified in 11 patients from 8 unrelated families and cause early-onset progressive sensorimotor peripheral neuropathy. Unlike known biallelic Pol III disorders, no white matter abnormalities were observed on brain MRI. Functional studies in patient-derived cells revealed dysregulation of Pol III targets and global tRNA pool depletion, without alterations in protein expression or localization. This work expands the Pol III disease spectrum beyond biallelic phenotypes and establishes POLR3A as a novel peripheral neuropathy gene, immediately addable to diagnostic panels.

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The discovery of a monoallelic mechanism for POLR3A opens a new diagnostic category distinct from the classical biallelic leukodystrophy forms. The correlation between tRNA depletion and peripheral neurodegeneration strengthens the RNA metabolism-neuropathy axis — a promising therapeutic target. This gene should be promptly added to hereditary neuropathy diagnostic panels.