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POLR3B
RNA polymerase III subunit B
POLR3B is located on the long (q) arm of chromosome 12, at band 12q23.3. Arm ratio per GRCh38 - banding schematic.
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Overview
POLR3B encodes the second-largest subunit of RNA polymerase III, a multi-protein enzyme complex responsible for transcribing several essential non-coding RNA species. This enzyme produces transfer RNA molecules that carry amino acids during protein assembly, as well as ribosomal RNA components that form the protein-synthesis machinery itself. Proper function of RNA polymerase III is fundamental to cellular metabolism, as protein production depends on a continuous supply of these RNA molecules.
Pathogenic variants in POLR3B impair the enzyme's transcriptional activity, leading to insufficient production of transfer and ribosomal RNAs. This deficiency particularly affects the nervous system, where reduced RNA polymerase III function interferes with myelin formation and maintenance. The gene is clinically significant in neurogenetics, with variant testing included in multiple NHS diagnostic panels for white matter disorders and developmental conditions.
What the gene does
The POLR3B protein functions as a core structural and catalytic component of the RNA polymerase III complex, which binds to specific DNA sequences and synthesises RNA according to the genetic template. This enzyme specifically transcribes genes encoding transfer RNAs, which serve as adaptors linking messenger RNA codons to their corresponding amino acids during translation. RNA polymerase III also produces 5S ribosomal RNA, a structural component of ribosomes, as well as other small RNAs involved in RNA processing and protein trafficking.
The POLR3B subunit contributes to the enzyme's catalytic core, participating in DNA binding and the positioning of the active site for RNA synthesis. The protein works in concert with other polymerase subunits to ensure accurate transcription initiation, elongation, and termination. Because transfer and ribosomal RNAs are required in high abundance across all cell types, RNA polymerase III activity must be tightly regulated to match cellular demand. Disruption of POLR3B function reduces the overall capacity for RNA polymerase III transcription, creating a bottleneck in protein synthesis that proves particularly detrimental to metabolically active tissues such as brain white matter.
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Chromosome location
POLR3B is located on chromosome 12 at cytogenetic band 12q23.3, in the long arm of the chromosome. This chromosomal region contains numerous genes involved in developmental and metabolic processes. The gene spans multiple exons encoding a 1,133-amino-acid protein, with the coding sequence distributed across the genomic locus in a pattern typical of large multi-domain enzymes.
Protein structure
The POLR3B protein comprises 1,133 amino acids and forms part of the multi-subunit RNA polymerase III enzyme complex. The protein contains a C4-type zinc finger domain spanning amino acids 1,080 to 1,095, located near the C-terminus. This zinc finger motif typically coordinates zinc ions to stabilise protein structure and may contribute to nucleic acid binding or protein-protein interactions within the polymerase complex. The overall architecture of POLR3B allows it to integrate into the catalytic core of RNA polymerase III alongside other subunits, forming the channels and clefts necessary for DNA template binding and RNA synthesis.
Key variants
Pathogenic variants in POLR3B are predominantly loss-of-function changes that reduce RNA polymerase III activity. At least 54 different POLR3B variants have been associated with neurological disease, including missense substitutions that impair protein folding or catalytic function, as well as truncating variants that produce shortened, non-functional proteins. Most affected individuals carry biallelic variants, inheriting one altered copy from each parent, consistent with autosomal recessive inheritance. The specific position and nature of variants can influence disease severity and clinical presentation.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Pathogenic variants in POLR3B cause Pol III-related leukodystrophy (also known as 4H leukodystrophy), an autosomal recessive neurological disorder characterised by abnormal white matter development in the brain. Leukodystrophies involve defects in myelin, the fatty insulating sheath surrounding nerve fibres that enables rapid signal transmission. Individuals with Pol III-related leukodystrophy typically present with a combination of hypomyelination (reduced myelin formation), hypodontia (missing teeth), hypogonadotropic hypogonadism (delayed or absent puberty), and other neurological features. The condition's severity and specific symptoms vary among affected individuals, reflecting differences in residual RNA polymerase III function.
- Pol III-related leukodystrophy (4H) Dedicated page coming soon
UK clinical status
POLR3B is included on multiple NHS Genomic Medicine Service gene panels, reflecting its established role in inherited neurological conditions. The gene holds green (diagnostic-grade evidence) classification on the Adult Onset Leukodystrophy panel (R62), the Ataxia and Cerebellar Anomalies panel, and the Inherited White Matter Disorders panel. It also appears on the Intellectual Disability panel (R29), the Hereditary Neuropathy or Pain Disorder panel (R78), and the Fetal Anomalies panel (R21). These panel memberships indicate that POLR3B testing is available through NHS genomic testing pathways for individuals presenting with relevant clinical features, such as progressive neurological decline, movement disorders, or developmental delay with white matter abnormalities on brain imaging.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the POLR3B gene do?
POLR3B encodes a core subunit of RNA polymerase III, the enzyme responsible for producing transfer RNAs and ribosomal RNAs essential for protein synthesis. These RNA molecules enable cells to translate genetic instructions into functional proteins throughout the body.
How is Pol III-related leukodystrophy inherited?
Pol III-related leukodystrophy follows autosomal recessive inheritance, meaning an affected individual inherits one pathogenic POLR3B variant from each parent. Parents who each carry one altered copy typically do not show symptoms but have a 25% chance with each pregnancy of having an affected child.
Is POLR3B testing available on the NHS?
Yes, POLR3B testing is available through NHS genomic testing pathways for individuals meeting clinical criteria on multiple diagnostic panels, including those for leukodystrophy, ataxia, intellectual disability, and white matter disorders. A healthcare provider can determine eligibility based on clinical presentation and family history.