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GCSH
glycine cleavage system protein H
The GCSH gene provides instructions for a protein crucial to the glycine cleavage system, which processes the amino acid glycine within the body. The GCSH gene encodes the H-protein subunit of the mitochondrial glycine cleavage system.
GCSH is located on the long (q) arm of chromosome 16, at band 16q23.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The GCSH gene is responsible for producing the H-protein, an essential component of the glycine cleavage system (GCS). This multi-enzyme complex is located in the mitochondria, the energy-producing organelles within cells. The GCS plays a critical role in metabolising glycine, a non-essential amino acid, by breaking it down into other compounds.
Proper function of the GCS is necessary for maintaining glycine homeostasis. Imbalances in this system, often due to variants in genes like GCSH, can lead to serious health conditions that disrupt normal metabolic processes.
What the gene does
The GCSH gene encodes the H-protein, a central component of the glycine cleavage system (GCS). The GCS is a complex of four distinct proteins that work together to break down glycine. The H-protein acts as an intermediary, carrying a lipoamide co-factor that transfers chemical groups derived from glycine during its degradation.
Specifically, the H-protein accepts the methylamine group from glycine and transfers it to other components within the GCS. This transfer is a crucial step in the overall catabolism of glycine, converting it into carbon dioxide, ammonia, and a one-carbon unit that can be used in other metabolic pathways, such as folate metabolism. The efficient operation of the GCS, facilitated by the GCSH protein, prevents the harmful accumulation of glycine.
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Chromosome location
The GCSH gene is situated on chromosome 16. Its specific location is at band 16q23.2, meaning it is found on the long (q) arm of chromosome 16, within region 23 and sub-band 2. This genomic position helps define the gene's physical address within the human genome.
Protein structure
The GCSH protein is composed of 173 amino acids. A key functional region described within the GCSH protein is the Lipoyl-binding domain, spanning amino acids 66-148. This domain is responsible for covalently attaching a lipoic acid co-factor, which is vital for the H-protein's role as a carrier within the glycine cleavage system.
Key variants
Variants in the GCSH gene can affect the structure and function of the H-protein. These genetic changes can lead to a reduced ability of the glycine cleavage system to process glycine efficiently. As a result, glycine can accumulate in the body, potentially reaching toxic levels that disrupt normal biological processes and lead to specific health conditions.
Sample of pathogenic variants
9 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.226C>T | p.Gln76Ter | Pathogenic/Likely pathogenic | ★★☆☆ | GCSH-related disorder |
c.293-2_293-1insT | - | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple mitochondrial dysfunctions syndrome 7 |
g.(?_81082846)_(81096298_?)del | - | Pathogenic | ★☆☆☆ | Glycine encephalopathy |
g.(?_81121196)_(81129883_?)del | - | Pathogenic | ★☆☆☆ | Glycine encephalopathy |
c.338_342del | p.Tyr113fs | Pathogenic | ★☆☆☆ | Glycine encephalopathy |
g.(5246_10695)_(10776_13711)del | - | Pathogenic | - | Multiple mitochondrial dysfunctions syndrome 7 |
c.170A>G | p.His57Arg | Pathogenic | - | Multiple mitochondrial dysfunctions syndrome 7 |
c.293-60_*72dup | - | Pathogenic | - | Multiple mitochondrial dysfunctions syndrome 7 |
c.344C>T | p.Pro115Leu | Pathogenic | - | Multiple mitochondrial dysfunctions syndrome 7 |
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 GCSH gene are associated with an inherited metabolic disorder called Nonketotic hyperglycinaemia. 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 develop the condition. Nonketotic hyperglycinaemia is characterised by abnormally high levels of glycine in the brain and cerebrospinal fluid, which can have significant neurological consequences.
Inheritance pattern
Conditions caused by pathogenic GCSH 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 GCSH gene is included in several UK NHS national genomic testing panels, indicating its clinical relevance in the UK. It holds a 'green' status on the DDG2P panel, and is also covered by panels for Early onset or syndromic epilepsy (R59), Intellectual disability (R29), and Likely inborn error of metabolism (R98). This inclusion supports its role in the investigation of various clinical presentations within the NHS Genomic Medicine Service.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the GCSH gene?
The GCSH gene provides instructions for the H-protein, which is a key component of the glycine cleavage system. This system is responsible for breaking down the amino acid glycine in the body.
What condition is associated with GCSH gene variants?
Variants in the GCSH gene are associated with Nonketotic hyperglycinaemia. This is an inherited metabolic disorder characterised by excessive accumulation of glycine due to impaired breakdown.
How is Nonketotic hyperglycinaemia inherited?
Nonketotic hyperglycinaemia caused by GCSH variants is inherited in an autosomal recessive pattern. This means an individual must inherit two affected copies of the GCSH gene, one from each parent, to develop the condition.