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IDH3B
isocitrate dehydrogenase (NAD(+)) 3 non-catalytic subunit beta
IDH3B is located on the short (p) arm of chromosome 20, at band 20p13. Arm ratio per GRCh38 - banding schematic.
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Overview
IDH3B encodes the non-catalytic beta subunit of the NAD-dependent isocitrate dehydrogenase 3 enzyme complex, which operates within mitochondria. This enzyme complex catalyses a critical step in the citric acid cycle, converting isocitrate to alpha-ketoglutarate whilst generating NADH, a molecule that drives cellular energy production. Although IDH3B itself does not perform the catalytic reaction, it plays an essential regulatory role in stabilising the enzyme complex and modulating its activity.
The protein encoded by IDH3B consists of 385 amino acids and works alongside other subunits to form the functional enzyme complex. Disruptions to IDH3B can impair mitochondrial metabolism, affecting tissues with high energy requirements. The gene has been included in clinical screening panels for retinal disorders, reflecting its relevance to inherited eye conditions.
What the gene does
The IDH3B protein serves as a regulatory component of the isocitrate dehydrogenase 3 complex, which comprises multiple subunits that together perform a key reaction in the citric acid cycle. This metabolic pathway occurs in the mitochondrial matrix and is fundamental to extracting energy from nutrients. The enzyme complex converts isocitrate into alpha-ketoglutarate, releasing carbon dioxide and reducing NAD+ to NADH in the process.
Whilst the catalytic subunits carry out the chemical transformation, the beta subunit encoded by IDH3B contributes to the structural integrity and regulatory control of the complex. It helps maintain the correct spatial arrangement of the catalytic sites and may influence how the enzyme responds to cellular signals regarding energy status. The NADH molecules generated by this reaction feed into the electron transport chain, driving ATP synthesis that powers cellular processes. Tissues with substantial metabolic demands, including the retina, rely heavily on efficient citric acid cycle function to sustain their activity.
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Chromosome location
IDH3B is located on the short arm of chromosome 20 at position p13, designated as 20p13. This chromosomal region contains numerous genes involved in diverse cellular functions. The precise genomic coordinates and exon structure of IDH3B determine how the gene is transcribed and processed into messenger RNA, which is then translated into the beta subunit protein within cells.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The IDH3B polypeptide of 385 amino acids folds into a three-dimensional structure that enables it to interact with other subunits of the isocitrate dehydrogenase 3 complex. The protein must adopt a conformation that allows stable assembly with catalytic and other regulatory subunits, forming a functional enzyme complex capable of coordinating the isocitrate-to-alpha-ketoglutarate reaction. Structural features that mediate subunit-subunit interactions are critical for maintaining enzyme stability and activity, though specific domain boundaries have not been formally defined in annotation databases.
Key variants
Genetic variants in IDH3B can alter the amino acid sequence of the beta subunit, potentially affecting how well the isocitrate dehydrogenase 3 complex assembles or functions. Changes that disrupt the protein's ability to interact with partner subunits or to stabilise the enzyme complex may impair mitochondrial metabolism. The clinical significance of individual variants is assessed based on their predicted impact on protein structure and function, alongside evidence from affected individuals and families.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.115C>T | p.Gln39Ter | Pathogenic/Likely pathogenic | ★★☆☆ | IDH3B-related disorders |
c.184G>T | p.Glu62Ter | Pathogenic/Likely pathogenic | ★★☆☆ | IDH3B-related disorders |
c.490C>T | p.Arg164Ter | Pathogenic/Likely pathogenic | ★★☆☆ | IDH3B-related disorders |
c.551_554del | p.Glu184fs | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 46 |
c.571C>T | p.Arg191Ter | Pathogenic/Likely pathogenic | ★★☆☆ | IDH3B-related disorders |
g.2663759del | - | Pathogenic | ★☆☆☆ | not provided |
c.128_138del | p.Val43fs | Pathogenic | ★☆☆☆ | not provided |
c.691C>T | p.Gln231Ter | Pathogenic | ★☆☆☆ | not provided |
c.937C>T | p.Gln313Ter | Pathogenic | ★☆☆☆ | not provided |
c.589del | p.Ile197fs | Pathogenic | - | Retinitis pigmentosa 46 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Changes in IDH3B have been associated with retinal disorders, reflecting the high metabolic demands of photoreceptor cells and other retinal tissues. The retina requires continuous energy production to maintain visual processing, and impaired mitochondrial function can lead to progressive degeneration of retinal cells. The specific phenotypes linked to IDH3B variants may vary depending on the nature and severity of the underlying genetic change, with some variants causing more pronounced effects on enzyme activity than others.
No disease links recorded for this gene in our reference set.
UK clinical status
IDH3B is included on the NHS Genomic Medicine Service Retinal Disorders panel, which guides diagnostic genetic testing for inherited eye conditions. The gene holds green classification on this panel (R32), indicating sufficient evidence to support its use in clinical diagnostics for retinal disease. This classification reflects expert consensus that variants in IDH3B can contribute to retinal pathology and warrant evaluation in individuals undergoing genetic investigation for vision problems.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the IDH3B gene do?
IDH3B provides instructions for making a regulatory subunit of the mitochondrial isocitrate dehydrogenase 3 enzyme complex, which plays a key role in the citric acid cycle. This metabolic pathway generates energy in the form of NADH, supporting cellular functions throughout the body.
How are IDH3B variants inherited?
Inheritance patterns for IDH3B-related conditions can vary depending on the specific variant and associated phenotype. Genetic counselling can help clarify the inheritance pattern relevant to a particular family and explain implications for relatives.
Why is IDH3B relevant to retinal health?
The retina has exceptionally high metabolic demands due to continuous light detection and signal processing. Because IDH3B contributes to mitochondrial energy production, variants that reduce enzyme function can impair retinal cell metabolism, potentially leading to progressive vision loss.