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PDHX
pyruvate dehydrogenase complex component X
The PDHX gene provides instructions for a key component of the pyruvate dehydrogenase complex, which is vital for converting food energy into a usable form for cells. The PDHX gene encodes the E3 binding protein, an integral part of the pyruvate dehydrogenase complex.
PDHX is located on the short (p) arm of chromosome 11, at band 11p13. Arm ratio per GRCh38 - banding schematic.
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Overview
The PDHX gene, or pyruvate dehydrogenase complex component X, plays a critical role in cellular metabolism. It provides the genetic blueprint for a protein known as the E3 binding protein, which is an essential part of the pyruvate dehydrogenase complex (PDC).
This complex is fundamental for converting energy derived from carbohydrates into a form that cells can readily use. Disruptions to the PDHX gene can impair the function of this vital complex, leading to metabolic issues.
What the gene does
The PDHX gene is responsible for producing the E3 binding protein, a component of the multi-enzyme pyruvate dehydrogenase complex (PDC). This complex is composed of several enzymes and other proteins, working collaboratively to facilitate a crucial metabolic reaction. Specifically, the E3 binding protein acts to link the E3 enzyme to the main complex, ensuring its correct structure and enabling it to function efficiently.
The PDC is instrumental in the pathways that convert the energy obtained from food into adenosine triphosphate (ATP), the primary energy currency of the cell. Within this process, the complex converts pyruvate, a molecule resulting from carbohydrate breakdown, into acetyl-CoA. This conversion is a necessary initiating step for the subsequent series of biochemical reactions that generate ATP, powering various cellular activities.
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Chromosome location
The PDHX gene is located on chromosome 11 at position 11p13. This specific chromosomal location helps to define its position within the human genome. The gene spans a region on the short arm of chromosome 11.
Protein structure
The PDHX protein is 501 amino acids long and features several distinct structural elements. It includes a Lipoyl-binding domain, found between amino acids 56 and 132, which is important for coenzyme attachment. A Disordered region is present from amino acids 142-175. Following this is a Peripheral subunit-binding (PSBD) domain, spanning amino acids 183-220, which facilitates interactions with other components of the pyruvate dehydrogenase complex. Another Disordered region is located between amino acids 225 and 268.
Key variants
Variants in the PDHX gene can alter the structure or function of the E3 binding protein, potentially impacting the overall efficiency of the pyruvate dehydrogenase complex. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions, and their effects can vary depending on the specific alteration.
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.1231C>T | p.Gln411Ter | Pathogenic/Likely pathogenic | ★★☆☆ | PDHX-related disorder |
c.1336C>T | p.Arg446Ter | Pathogenic/Likely pathogenic | ★★☆☆ | PDHX-related disorders |
c.419_420del | p.His140fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3-binding protein deficiency |
c.557del | p.Pro186fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3-binding protein deficiency |
c.711dup | p.Thr238fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3-binding protein deficiency |
c.742C>T | p.Gln248Ter | Pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3-binding protein deficiency |
c.793dup | p.Thr265fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3-binding protein deficiency |
c.850C>T | p.Arg284Ter | Pathogenic | ★★☆☆ | Pyruvate dehydrogenase E3-binding protein deficiency |
c.1125_1126insATAA | p.Pro376fs | Pathogenic | ★☆☆☆ | Pyruvate dehydrogenase E3-binding protein deficiency |
c.1311del | p.Cys438fs | Pathogenic | ★☆☆☆ | not provided |
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
Pathogenic variants in the PDHX gene are associated with conditions that affect metabolism. One such condition is pyruvate dehydrogenase deficiency, where mutations can lead to a complete absence of the E3 binding protein. This deficiency can result in a dangerous accumulation of lactic acid in the body, known as lactic acidosis, alongside developmental delays and neurological problems. PDHX variants have also been implicated in Leigh syndrome.
No disease links recorded for this gene in our reference set.
UK clinical status
In the UK, the PDHX gene is included in several NHS Genomic Medicine Service national testing panels, indicating its clinical significance. It is listed on panels for "Dystonia, chorea or related movement disorder, childhood onset" (R57), "Early onset or syndromic epilepsy", "Foetal anomalies" (R21), "Intellectual disability", "Likely inborn error of metabolism" (R98), "Mitochondrial disorders", "Possible mitochondrial disorder, nuclear genes" (R63), "Pyruvate dehydrogenase (PDH) deficiency" (R316), and "Undiagnosed metabolic disorders". This inclusion highlights its relevance for diagnosing a range of inherited metabolic and neurological conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the PDHX gene?
The PDHX gene provides instructions for making the E3 binding protein, which is a vital part of the pyruvate dehydrogenase complex. This complex is crucial for converting carbohydrates into a usable energy form for cells.
What conditions are associated with variants in the PDHX gene?
Variants in the PDHX gene are primarily associated with pyruvate dehydrogenase deficiency, a metabolic disorder that can lead to lactic acidosis, developmental delays, and neurological issues. It has also been linked to Leigh syndrome.
Is the PDHX gene included in UK genetic testing panels?
Yes, the PDHX gene is included in several NHS Genomic Medicine Service national testing panels. These cover conditions such as pyruvate dehydrogenase deficiency, mitochondrial disorders, and early-onset neurological syndromes.
References
- Patel MS, Korotchkina LG, Sidhu S. Interaction of E1 and E3 components with the core proteins of the human pyruvate dehydrogenase complex. Journal of molecular catalysis. B, Enzymatic. 2009. PMID: 20160912
- Smolle M, Prior AE, Brown AE. A new level of architectural complexity in the human pyruvate dehydrogenase complex. The Journal of biological chemistry. 2006. PMID: 16679318
- Brown RM, Head RA, Morris AA. Pyruvate dehydrogenase E3 binding protein (protein X) deficiency. Developmental medicine and child neurology. 2006. PMID: 16904023
- Brown RM, Head RA, Brown GK. Pyruvate dehydrogenase E3 binding protein deficiency. Human genetics. 2002. PMID: 11935326
- Adam MP, Bick S, Mirzaa GM. Primary Pyruvate Dehydrogenase Complex Deficiency Overview. 1993. PMID: 34138529