Monoallelic POLR3A Variants Cause Early-Onset Peripheral Neuropathy.
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Ramos Luiza L P, Parmar Jevin M, Wijngaard Robin, Grosz Bianca R, Lazar Tamas, Mateiu Ligia, Vucic Steve, Kumar Kishore R, Yeow Dennis, Rudaks Laura I, de Boer Lonneke, de Vreugd Annemarie, Koolen David A, Gardeitchik Thatjana, Cairns Anita, Iyengar Krishnan, Kok Fernando, Figueiredo Fernanda Barbosa, de Siqueira Carvalho Alzira Alves, Mageste Barbosa Luiz S, Arantes Rodrigo Rezende, Rehbein Tyler, Bontrager Jordan E, Wood Elizabeth P, Sowden Janet E, Monahan Gavin, Kumaheri Meutia, Cuijt Ivy, Ellis Melina, Perez-Siles Gonzalo, McNamara Elyshia, van Beek Ronald, Meijers Celine B, Tournev Ivaylo, Zuchner Stephan, Wodak Shoshana J, van Karnebeek Clara D M, Laing Nigel, Semcesen Liana N, Stroud David A, Herrmann David N, Guergueltcheva Velina, Kennerson Marina L, Oud Machteld M, Ravenscroft Gianina, Candayan Ayse, Jordanova Albena
Аннотация
METHODS: We performed clinical and genetic investigation of the affected families. Biophysical characterization of mutant proteins was performed in silico. Immunoblotting, interactomics, and transcriptomics characterization were done in cellular models.
RESULTS: We identified 11 patients across 8 unrelated families harboring heterozygous missense variants in POLR3A, occurring de novo or segregating in an autosomal-dominant fashion. The patients presented with an early-onset, progressive sensorimotor peripheral polyneuropathy with intermediate to demyelinating ranges of nerve conduction slowing, occasionally accompanied with neurological or non-neurological features. White matter abnormalities, characteristic for the biallelic Pol III-related disorders, where not observed in the brain magnetic resonance imaging (MRI) evaluations. The neuropathy-associated variants cluster in regions critical for Pol III activity. We observed mis-regulation of individual Pol III targets and global downregulation of tRNA pools in patient-derived cells. This Pol III dysfunction was not due to impaired POLR3A expression, subcellular localization, or subunit interactions.
INTERPRETATION: Our findings expand the Pol III-related disease spectrum beyond the known biallelic phenotypes and establish POLR3A as a novel peripheral neuropathy-associated gene. This work highlights a central role of Pol III dysfunction in disease and reinforces the link between tRNA metabolism and peripheral neurodegeneration. ANN NEUROL 2026;100:655-671.