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GCDH
glutaryl-CoA dehydrogenase
The GCDH gene provides instructions for producing glutaryl-CoA dehydrogenase, an enzyme crucial for breaking down certain amino acids within the body's cells. The GCDH gene plays a vital role in metabolism by encoding an enzyme called glutaryl-CoA dehydrogenase.
GCDH is located on the short (p) arm of chromosome 19, at band 19p13.13. Arm ratio per GRCh38 - banding schematic.
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Overview
The GCDH gene, or glutaryl-CoA dehydrogenase, is integral to human metabolism. It provides the genetic blueprint for an enzyme found within the mitochondria, the energy-producing compartments of cells. This enzyme is specifically involved in the breakdown pathways of the amino acids lysine, hydroxylysine, and tryptophan, which are fundamental building blocks of proteins.
What the gene does
The enzyme produced from the GCDH gene, glutaryl-CoA dehydrogenase, performs a critical function within cellular mitochondria. It facilitates a step in the metabolic process that breaks down the amino acids lysine, hydroxylysine, and tryptophan. When this enzyme is deficient or non-functional due to genetic changes in GCDH, these amino acids and their intermediate breakdown products can accumulate to toxic levels. This accumulation can be particularly damaging to the nervous system, especially when the body experiences stress or illness, leading to various health issues.
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Chromosome location
The GCDH gene is situated on the short arm of chromosome 19, specifically at position 19p13.13. This chromosomal location indicates where the gene is physically mapped within the human genome.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variations within the GCDH gene can impact the structure and function of the glutaryl-CoA dehydrogenase enzyme. These genetic changes can range from small point mutations to larger deletions, all of which may alter the enzyme's ability to process amino acids effectively.
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.1000A>T | p.Lys334Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glutaric aciduria, type 1 |
c.1075C>T | p.Gln359Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glutaric aciduria, type 1 |
c.1168G>T | p.Gly390Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Glutaric aciduria, type 1 |
c.1169G>A | p.Gly390Glu | Pathogenic/Likely pathogenic | ★★☆☆ | Glutaric aciduria, type 1 |
c.1193A>G | p.Tyr398Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Glutaric aciduria, type 1 |
c.561C>A | p.Asp187Glu | Pathogenic/Likely pathogenic | ★★☆☆ | GCDH-related disorder |
c.636G>A | p.Trp212Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glutaric aciduria, type 1 |
c.763T>C | p.Ser255Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Glutaric aciduria, type 1 |
c.764C>A | p.Ser255Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glutaric aciduria, type 1 |
c.961C>T | p.Gln321Ter | Pathogenic | ★★☆☆ | Glutaric aciduria, type 1 |
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 GCDH gene are primarily associated with an inherited metabolic disorder called Glutaric aciduria type 1. This condition is inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to be affected.
Inheritance pattern
Conditions caused by pathogenic GCDH variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The GCDH gene is recognised within several NHS Genomic Medicine Service clinical panels, indicating its importance in genetic testing in the UK. It is listed in DDG2P, and specifically for conditions such as Glutaric acidaemia type 1 - Diagnostic (R449), Foetal anomalies (R21), and Dystonia, chorea or related movement disorder, childhood onset (R57). The gene is also included in panels for Intellectual disability, Leukodystrophy (adult onset), Structural basal ganglia disorders, and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the GCDH gene?
The GCDH gene provides instructions for making an enzyme called glutaryl-CoA dehydrogenase, which is crucial for breaking down the amino acids lysine, hydroxylysine, and tryptophan in the mitochondria of cells.
What happens if the GCDH gene is not working correctly?
If the GCDH gene is not functioning properly, it can lead to a deficiency in the glutaryl-CoA dehydrogenase enzyme. This causes a build-up of certain amino acids and their by-products, which can be toxic, particularly to the nervous system.
What condition is associated with variants in the GCDH gene?
Pathogenic variants in the GCDH gene are associated with Glutaric aciduria type 1, an autosomal recessive inherited metabolic disorder.
References
- Basinger AA, Booker JK, Frazier DM. Glutaric acidemia type 1 in patients of Lumbee heritage from North Carolina. Molecular genetics and metabolism. 2006. PMID: 16466958
- Hedlund GL, Longo N, Pasquali M. Glutaric acidemia type 1. American journal of medical genetics. Part C, Seminars in medical genetics. 2006. PMID: 16602100
- Kölker S, Garbade SF, Greenberg CR. Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatric research. 2006. PMID: 16641220
- Kölker S, Hoffmann GF, Schor DS. Glutaryl-CoA dehydrogenase deficiency: region-specific analysis of organic acids and acylcarnitines in post mortem brain predicts vulnerability of the putamen. Neuropediatrics. 2003. PMID: 14598231
- Greenberg CR, Prasad AN, Dilling LA. Outcome of the first 3-years of a DNA-based neonatal screening program for glutaric acidemia type 1 in Manitoba and northwestern Ontario, Canada. Molecular genetics and metabolism. 2002. PMID: 11825066
- Tang NL, Hui J, Law LK. Recurrent and novel mutations of GCDH gene in Chinese glutaric acidemia type I families. Human mutation. 2000. PMID: 11058907
- Busquets C, Soriano M, de Almeida IT. Mutation analysis of the GCDH gene in Italian and Portuguese patients with glutaric aciduria type I. Molecular genetics and metabolism. 2000. PMID: 11073722
- Goodman SI, Stein DE, Schlesinger S. Glutaryl-CoA dehydrogenase mutations in glutaric acidemia (type I): review and report of thirty novel mutations. Human mutation. 1998. PMID: 9711871