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GLDC
glycine decarboxylase
The *GLDC* gene provides instructions for making the glycine decarboxylase enzyme, a critical component of the glycine cleavage system responsible for breaking down glycine in the body. The *GLDC* gene codes for an enzyme called glycine decarboxylase, also known as the P-protein.
GLDC is located on the short (p) arm of chromosome 9, at band 9p24.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The *GLDC* gene contains the genetic blueprint for glycine decarboxylase, an enzyme fundamental to the body's glycine cleavage system. This system is located within the mitochondria of cells, where it orchestrates the breakdown of glycine, an amino acid and neurotransmitter. Effective glycine metabolism is crucial for the normal development and operation of nerve cells, particularly in the brain.
Disruptions to the *GLDC* gene can lead to conditions such as Nonketotic Hyperglycinaemia, highlighting its importance in metabolic and neurological health.
What the gene does
The glycine decarboxylase enzyme, encoded by the *GLDC* gene, is a pivotal component of the glycine cleavage system. This enzyme works alongside three other proteins within cellular mitochondria to break down excess glycine. Glycine, an amino acid, serves as a building block for proteins and functions as a chemical messenger (neurotransmitter) in the brain.
The breakdown process facilitated by the glycine cleavage system is essential for maintaining appropriate glycine levels, which in turn supports the healthy development and function of nerve cells. Additionally, this process generates a methyl group that is utilised by folate, a vitamin critical for various cellular functions, including brain development.
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Chromosome location
The *GLDC* gene is situated on chromosome 9, specifically at position 9p24.1. This precise location on the short arm of chromosome 9 determines where the genetic instructions for glycine decarboxylase are found within the human genome.
Protein structure
The glycine decarboxylase protein, comprising 1020 amino acids, exhibits a specific region of structural flexibility. A 'Disordered' region has been identified within the protein, spanning amino acids 21-46. This disordered segment suggests a lack of fixed three-dimensional structure, which can be important for protein-protein interactions or regulatory mechanisms.
Key variants
Variants within the *GLDC* gene can influence the production or function of the glycine decarboxylase enzyme. These genetic changes can range from single nucleotide alterations to larger deletions or insertions, potentially affecting the enzyme's ability to process glycine effectively. Understanding these variants is key to comprehending their impact on metabolic health.
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.1194C>G | p.Tyr398Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glycine encephalopathy 1 |
c.2183G>A | p.Gly728Glu | Pathogenic | ★★☆☆ | Glycine encephalopathy |
c.2654T>C | p.Leu885Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Glycine encephalopathy |
c.2680A>G | p.Thr894Ala | Pathogenic/Likely pathogenic | ★★☆☆ | Glycine encephalopathy |
c.846_847del | p.Arg282fs | Pathogenic | ★★☆☆ | Glycine encephalopathy |
GRCh37/hg19 9p24.1(chr9:6637871-6701130)x1 | - | Pathogenic | ★☆☆☆ | not specified |
c.2309_2310delinsA | p.Ile770fs | Pathogenic | ★☆☆☆ | Glycine encephalopathy |
c.2665+2T>C | - | Pathogenic | ★☆☆☆ | Glycine encephalopathy 1 |
c.382del | p.Gln128fs | Pathogenic | ★☆☆☆ | Glycine encephalopathy |
c.533dup | p.Asn178fs | Pathogenic | ★☆☆☆ | Glycine encephalopathy |
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 *GLDC* gene are a significant cause of Nonketotic Hyperglycinaemia. This inherited metabolic disorder is characterised by abnormally elevated levels of glycine in the body, leading to severe neurological complications. *GLDC* gene variants are implicated in approximately 80% of all diagnosed cases of Nonketotic Hyperglycinaemia.
Inheritance pattern
Conditions caused by pathogenic GLDC 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 *GLDC* gene is featured on several UK NHS national genomic test directories, indicating its clinical relevance for genetic testing in the UK. It is included on panels for conditions such as Early Onset or Syndromic Epilepsy, Foetal Anomalies (R21), Intellectual Disability, Likely Inborn Error of Metabolism (R98), and Undiagnosed Metabolic Disorders. It is also listed on the DDG2P panel, which catalogues genes associated with developmental disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the *GLDC* gene?
The *GLDC* gene provides instructions for the glycine decarboxylase enzyme, a critical part of the glycine cleavage system. This system breaks down excess glycine, an amino acid and neurotransmitter, within cellular mitochondria, which is vital for normal nerve cell function.
Which condition is primarily associated with variants in the *GLDC* gene?
Variants in the *GLDC* gene are primarily associated with Nonketotic Hyperglycinaemia. This is a severe inherited metabolic disorder characterised by dangerously high levels of glycine in the body, leading to significant neurological problems.
Where is the *GLDC* gene located in the human genome?
The *GLDC* gene is located on chromosome 9, specifically at position 9p24.1. This indicates its precise address within the human genetic code.
References
- Coughlin CR 2nd, Swanson MA, Kronquist K. The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT. Genetics in medicine : official journal of the American College of Medical Genetics. 2017. PMID: 27362913
- Swanson MA, Coughlin CR Jr, Scharer GH. Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia. Annals of neurology. 2015. PMID: 26179960
- Kikuchi G, Motokawa Y, Yoshida T. Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia. Proceedings of the Japan Academy. Series B, Physical and biological sciences. 2008. PMID: 18941301
- Applegarth DA, Toone JR. Glycine encephalopathy (nonketotic hyperglycinemia): comments and speculations. American journal of medical genetics. Part A. 2006. PMID: 16353254
- Kure S, Kato K, Dinopoulos A. Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia. Human mutation. 2006. PMID: 16450403
- Conter C, Rolland MO, Cheillan D. Genetic heterogeneity of the GLDC gene in 28 unrelated patients with glycine encephalopathy. Journal of inherited metabolic disease. 2006. PMID: 16601880
- Sellner L, Edkins E, Greed L. Detection of mutations in the glycine decarboxylase gene in patients with nonketotic hyperglycinaemia. Molecular genetics and metabolism. 2005. PMID: 15670722
- Nakai T, Nakagawa N, Maoka N. Structure of P-protein of the glycine cleavage system: implications for nonketotic hyperglycinemia. The EMBO journal. 2005. PMID: 15791207
- Dinopoulos A, Matsubara Y, Kure S. Atypical variants of nonketotic hyperglycinemia. Molecular genetics and metabolism. 2005. PMID: 16157495
- Adam MP, Bick S, Mirzaa GM. Nonketotic Hyperglycinemia. 1993. PMID: 20301531