ArticleAmerican journal of human genetics2011
Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy.
Article in American journal of human genetics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 146 papers, 1 of them a synthesis that pooled it.
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Who cites it
146 citing papers in PubMed, 1 synthesis or guideline pooled it, 267 citations in OpenAlex.
- Meta-Analysis of QTL Mapping and GWAS Reveal Candidate Genes for Heat Tolerance in Small Yellow Croaker,International journal of molecular sciences · 2025Pooled it
- Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin.The Journal of clinical investigation · 2016Trial
- White matter disorders at the intersection of transcription, RNA processing and translation.Nature reviews. Neurology · 2026Review
- Monoallelic POLR3A Variants Cause Early-Onset Peripheral Neuropathy.Annals of neurology · 2026Article
- Genetics of Idiopathic Hypogonadotropic HypogonadismJournal of clinical research in pediatric endocrinology · 2026Review
- RNA Polymerase III subunit Polr3a is required for craniofacial cartilage and bone development in zebrafish.PLoS genetics · 2026Article
- Expanding the genetic spectrum of neurogenetic disorders in moroccan families by exome sequencing: identification of candidate variants in RYR3, POLR3A, and LAMA2.Molecular biology reports · 2026Article
- RNA-based discovery and correction of splicing defects caused byMolecular therapy. Nucleic acids · 2026Article
- Targeting tRNA-Arg-TCT-4-1 suppresses cancer cell growth and tumorigenesis.bioRxiv : the preprint server for biology · 2026Article
- Study of POLR3A variants in a family trio suggests mutation-specific pathogenetic mechanisms: insights from integrative OMIC approaches.Cell communication and signaling : CCS · 2026Article
- Article
- A scoping review of stem cell models of leukodystrophies: advances in understanding pathophysiological mechanisms.NPJ genomic medicine · 2025Article
- POLR3A rare variants in a patient with intellectual disability, ataxic gait and cortical malformations: a case-report.Italian journal of pediatrics · 2025Article
- Identification of Novel Genetic Variants in a Cohort of Congenital Hypogonadotropic Hypogonadism: Computational Analysis of Pathogenicity Predictions.International journal of molecular sciences · 2025Article
- POLR3-Related Leukodystrophy: A Qualitative Study on Parents' Experiences With the Health Care System.Pediatric neurology · 2025Article
- Bi-allelic variants in BRF2 are associated with perinatal death and craniofacial anomalies.Genome medicine · 2025Article
- Computational studies on the functional and structural impact of pathogenic mutations in enzymes.Protein science : a publication of the Protein Society · 2025Review
- The First Case of 4H Syndrome with Type 1 Diabetes MellitusJournal of clinical research in pediatric endocrinology · 2025Article
- Biallelic variants inBrain communications · 2025Article
- Stress and Quality of Life of Parents of Children With POLR3-Related Leukodystrophy: A Cross-Sectional Pilot Study.Journal of child neurology · 2025Article
86 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
19 authors at 7 institutions in 4 countries.
Funding
Abstract
Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterized by abnormal white matter visible by brain imaging. It is estimated that at least 30% to 40% of individuals remain without a precise diagnosis despite extensive investigations. We mapped tremor-ataxia with central hypomyelination (TACH) to 10q22.3-23.1 in French-Canadian families and sequenced candidate genes within this interval. Two missense and one insertion mutations in five individuals with TACH were uncovered in POLR3A, which codes for the largest subunit of RNA polymerase III (Pol III). Because these families were mapped to the same locus as leukodystrophy with oligodontia (LO) and presented clinical and radiological overlap with individuals with hypomyelination, hypodontia and hypogonadotropic hypogonadism (4H) syndrome, we sequenced this gene in nine individuals with 4H and eight with LO. In total, 14 recessive mutations were found in 19 individuals with TACH, 4H, or LO, establishing that these leukodystrophies are allelic. No individual was found to carry two nonsense mutations. Immunoblots on 4H fibroblasts and on the autopsied brain of an individual diagnosed with 4H documented a significant decrease in POLR3A levels, and there was a more significant decrease in the cerebral white matter compared to that in the cortex. Pol III has a wide set of target RNA transcripts, including all nuclear-coded tRNA. We hypothesize that the decrease in POLR3A leads to dysregulation of the expression of certain Pol III targets and thereby perturbs cytoplasmic protein synthesis. This type of broad alteration in protein synthesis is predicted to occur in other leukoencephalopathies such as hypomyelinating leukodystrophy-3, caused by mutations in aminoacyl-tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1).
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.