Evidence map›Paper›PMID 42260910›Full record

ArticleAnnals of neurology2026

Monoallelic POLR3A Variants Cause Early-Onset Peripheral Neuropathy.

Luiza L P Ramos, Jevin M Parmar, Robin Wijngaard, Bianca R Grosz, Tamas Lazar, Ligia Mateiu, Steve Vucic, Kishore R Kumar, Dennis Yeow, Laura I Rudaks and 37 more

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Article in Annals of neurology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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2 · The registry

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

47 authors.

Luiza L P RamosMolecular Neurogenomics Group, VIB Center for Molecular Neurology, Antwerp, Belgium.ORCID https://orcid.org/0000-0003-1668-1683
Jevin M ParmarHarry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.ORCID https://orcid.org/0000-0003-1864-8094
Robin WijngaardDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Bianca R GroszNorthcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales, Australia.ORCID https://orcid.org/0000-0002-6926-0551
Tamas LazarVIB-VUB Center for Structural Biology, VIB, Brussels, Belgium.ORCID https://orcid.org/0000-0001-7496-6711
Ligia MateiuDepartment of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Steve VucicBrain and Nerve Research Center, Concord Clinical School, University of Sydney, Sydney, New South Wales, Australia.ORCID https://orcid.org/0000-0002-8323-873X
Kishore R KumarNeurology Department and Molecular Medicine Laboratory, Concord Repatriation General Hospital, Sydney Local Health District and NSW Health Pathology, Sydney, New South Wales, Australia.ORCID https://orcid.org/0000-0003-3482-6962
Dennis YeowSchool of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia.
Laura I RudaksNeurology Department and Molecular Medicine Laboratory, Concord Repatriation General Hospital, Sydney Local Health District and NSW Health Pathology, Sydney, New South Wales, Australia.ORCID https://orcid.org/0000-0002-1100-319X
Lonneke de BoerDepartment of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands.ORCID https://orcid.org/0009-0007-7882-8747
Annemarie de VreugdUnited for Metabolic Diseases (UMD), Amsterdam, The Netherlands.ORCID https://orcid.org/0009-0000-3517-1764
David A KoolenDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Thatjana GardeitchikDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Anita CairnsNeurosciences Department, Queensland Children's Hospital, Brisbane, Queensland, Australia.ORCID https://orcid.org/0000-0002-7123-0351
Krishnan IyengarDepartment of Anatomical Pathology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
Fernando KokDepartment of Neurology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil.
Fernanda Barbosa FigueiredoMendelics Genomic Analysis, Sao Paulo, Brazil.ORCID https://orcid.org/0000-0001-7820-9574
Alzira Alves de Siqueira CarvalhoNeuromuscular Reference Center, Citadella Hospital, University of Liege, Liege, Belgium.ORCID https://orcid.org/0000-0002-5485-7937
Luiz S Mageste BarbosaNeuromuscular Disease Centre, Department of Neurology, University Hospital of the Federal University of Minas Gerais, Belo Horizonte, Brazil.
Rodrigo Rezende ArantesMedical Genetics Service, University Hospital of the Federal University of Minas Gerais, Belo Horizonte, Brazil.ORCID https://orcid.org/0000-0002-5041-1102
Tyler RehbeinDepartment of Neurology, University of Rochester, Rochester, NY.ORCID https://orcid.org/0000-0001-5815-0907
Jordan E BontragerDepartment of Neurology, University of Rochester, Rochester, NY.
Elizabeth P WoodDepartment of Neurology, University of Rochester, Rochester, NY.
Janet E SowdenDepartment of Neurology, University of Rochester, Rochester, NY.
Gavin MonahanHarry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.ORCID https://orcid.org/0000-0001-5062-5963
Meutia KumaheriGenomics Pillar, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Ivy CuijtMolecular Neurogenomics Group, VIB Center for Molecular Neurology, Antwerp, Belgium.ORCID https://orcid.org/0009-0006-9384-4764
Melina EllisNorthcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales, Australia.ORCID https://orcid.org/0000-0002-8542-048X
Gonzalo Perez-SilesNorthcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales, Australia.
Elyshia McNamaraHarry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.
Ronald van BeekDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Celine B MeijersDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Ivaylo TournevDepartment of Neurology, Clinic of Nervous Diseases, UMBAL Aleksandrovska, Medical University-Sofia, Sofia, Bulgaria.
Stephan ZuchnerDr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL.
Shoshana J WodakVIB-VUB Center for Structural Biology, VIB, Brussels, Belgium.ORCID https://orcid.org/0000-0002-0701-6545
Clara D M van KarnebeekUnited for Metabolic Diseases (UMD), Amsterdam, The Netherlands.
Nigel LaingHarry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.ORCID https://orcid.org/0000-0001-5111-3732
Liana N SemcesenDepartment of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
David A StroudMurdoch Children's Research Institute, Melbourne, Victoria, Australia.ORCID https://orcid.org/0000-0002-2048-3383
David N HerrmannDepartment of Neurology, University of Rochester, Rochester, NY.
Velina GuergueltchevaClinic of Neurology, University Hospital Sofiamed, Sofia, Bulgaria.
Marina L KennersonNorthcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales, Australia.ORCID https://orcid.org/0000-0003-3332-5074
Machteld M OudDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Gianina RavenscroftHarry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.ORCID https://orcid.org/0000-0003-3634-211X
Ayse CandayanMolecular Neurogenomics Group, VIB Center for Molecular Neurology, Antwerp, Belgium.ORCID https://orcid.org/0000-0002-3528-2293
Albena JordanovaMolecular Neurogenomics Group, VIB Center for Molecular Neurology, Antwerp, Belgium.ORCID https://orcid.org/0000-0002-3833-3754

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

objectiveBiallelic 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.

methodsWe 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.

resultsWe 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.

interpretationOur 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.

Indexed as

Peripheral Nervous System DiseasesRNA Polymerase IIIAdolescentAdultAge of OnsetAllelesChildFemaleHumansMaleMutation, MissensePedigreePOLR3A protein, humanRNA Polymerase III

Identifiers

PMID42260910
PMCPMC13495874

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