Monoallelic <scp> <i>POLR3A</i> </scp> Variants Cause Early‐Onset Peripheral Neuropathy

OBJECTIVE: Biallelic variants in genes encoding the RNA polymerase III complex (Pol III) cause a spectrum of neurological disorders primarily affecting the central nervous system. Monoallelic variants have been reported in the POLR3B subunit only, associated with neurodevelopmental disorder, epilepsy, and peripheral neuropathy. We describe a novel Pol III-related disorder caused by monoallelic variants in POLR3A and presenting primarily with peripheral neuropathy. 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.

Authors

Institutions

Publication Details

Journal
Annals of Neurology
Published
2026-06-08
DOI
https://doi.org/10.1002/ana.78268
Primary Topic
RNA regulation and disease
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Monoallelic POLR3A Variants Cause Early‐Onset Peripheral Neuropathy

Laura Ivete Rudaks, Alzira Alves de Siqueira Carvalho, Marina Kennerson, Gavin Monahan et al.
Annals of Neurology
RNA regulation and disease
article

Monoallelic POLR3A Variants Cause Early‐Onset Peripheral Neuropathy

Laura Ivete Rudaks, Alzira Alves de Siqueira Carvalho, Marina Kennerson, Gavin Monahan, Ayşe Candayan, David A. Stroud, Liana N. Semcesen, Nigel G. Laing, Ivy Cuijt, Thatjana Gardeitchik, Ronald van Beek, Jordan E. Bontrager, Robin Wijngaard, Elizabeth P. Wood, Fernanda Barbosa Figueiredo, Bianca R. Grosz, Tamás Lázár, Meutia Kumaheri, Fernando Kok, Anita Cairns, Rodrigo Rezende Arantes, Albena Jordanova, Gianina Ravenscroft, Janet E. Sowden, Melina Ellis, Kishore R. Kumar, J. Parmar, Tyler Rehbein, Dennis Yeow, A. de Vreugd, Luiza Ramos, Velina Guergueltcheva, Lonneke de Boer, Krishnan Iyengar, M S Oud, Ligia Mateiu, G Perez-Siles, Luiz S. Mageste Barbosa, David N. Herrmann, Shoshana J. Wodak, Stephan Zuchner, Clara D. M. van Karnebeek, Elyshia McNamara, Celine B. Meijers, David A. Koolen, Ivaylo Tournev, Steve Vucic
article en

Abstract

OBJECTIVE: Biallelic variants in genes encoding the RNA polymerase III complex (Pol III) cause a spectrum of neurological disorders primarily affecting the central nervous system. Monoallelic variants have been reported in the POLR3B subunit only, associated with neurodevelopmental disorder, epilepsy, and peripheral neuropathy. We describe a novel Pol III-related disorder caused by monoallelic variants in POLR3A and presenting primarily with peripheral neuropathy. 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.

Annals of Neurology
Universidade Federal de Minas Gerais (BR), New Bulgarian University (BG), The University of Sydney (AU), Vrije Universiteit Brussel (BE), Garvan Institute of Medical Research (AU), University of Miami (US), Radboud University Nijmegen (NL), University of Antwerp (BE), The University of Melbourne (AU), Universidade de São Paulo (BR), Royal Brisbane and Women's Hospital (AU), Harry Perkins Institute of Medical Research (AU), Royal North Shore Hospital (AU), Concord Repatriation General Hospital (AU), Radboud University Medical Center (NL), Medical University of Sofia (BG), UNSW Sydney (AU), Netherlands Center for Occupational Diseases (NL), Victorian Clinical Genetics Services (AU), St Vincent's Clinic (AU), Dr. John T. Macdonald Foundation (US), VIB-UAntwerp Center for Molecular Neurology (BE), Mendelics (BR), VIB-VUB Center for Structural Biology (BE), Hospital Universitário da Universidade de São Paulo (BR), Murdoch Children's Research Institute (AU), Anzac Research Institute (AU), Innovative Research (United States) (US), Centre hospitalier régional de la Citadelle (BE), Genomic (Brazil) (BR), Children's Health Queensland Hospital and Health Service (AU), University of Rochester (US), Sofia University "St. Kliment Ohridski" (BG), Universidade Federal do ABC (BR), University of Amsterdam (NL)
Good health and well-being
Openalex Percentile: Top 9%
RNA regulation and disease
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.