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CHAT
choline O-acetyltransferase
The CHAT gene provides instructions for making choline acetyltransferase, an enzyme crucial for producing acetylcholine, a neurotransmitter essential for muscle movement. The CHAT gene is integral to the nervous system, encoding an enzyme that synthesises acetylcholine.
CHAT is located on the long (q) arm of chromosome 10, at band 10q11.23. Arm ratio per GRCh38 - banding schematic.
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Overview
The CHAT gene, also known as choline O-acetyltransferase, plays a critical role in neuromuscular function. It contains the genetic blueprint for an enzyme that produces acetylcholine, a key chemical messenger in the body. This enzyme is primarily located at the junctions where nerve cells communicate with muscle cells.
Inheritance of conditions associated with CHAT is typically autosomal recessive, meaning an individual must inherit two copies of a variant gene - one from each parent - to be affected. CHAT is included in carrier screening panels due to its association with inherited conditions affecting muscle control.
What the gene does
The protein produced by the CHAT gene is choline acetyltransferase. This enzyme is responsible for the synthesis of acetylcholine, a vital neurotransmitter. Acetylcholine is generated within the presynaptic terminals, which are the ends of nerve cells.
Once synthesised, acetylcholine is released into the synaptic cleft, the space between nerve and muscle cells. It then binds to specific receptor proteins on the muscle cell membrane. This binding action triggers the opening of ion channels, allowing charged particles to flow into and out of the muscle cells. This ion movement is fundamental for initiating muscle contraction and subsequent relaxation, which underpins all muscle movement.
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Chromosome location
The CHAT gene is situated on chromosome 10, specifically at position 10q11.23. This chromosomal location indicates where the gene can be found within the human genome.
Protein structure
The CHAT protein, also known as choline acetyltransferase, consists of 748 amino acids. Its structural composition includes two notable disordered regions. One disordered region is located at the N-terminus of the protein, spanning amino acids 1-89. Another disordered region is found towards the C-terminus, from amino acids 727-748.
Key variants
Genetic variations within the CHAT gene can alter the production or function of the choline acetyltransferase enzyme. These changes can range from single base pair substitutions to larger deletions or insertions within the gene sequence. Such variants may lead to a reduced ability to synthesise acetylcholine, thereby disrupting nerve-muscle communication.
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.1027G>T | p.Glu343Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial infantile myasthenia |
c.1231G>T | p.Gly411Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial infantile myasthenia |
c.1359_1363del | p.Cys453_Glu455delinsTer | Pathogenic/Likely pathogenic | ★★☆☆ | Familial infantile myasthenia |
c.1387C>T | p.Gln463Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial infantile myasthenia |
c.1441dup | p.Arg481fs | Pathogenic/Likely pathogenic | ★★☆☆ | Familial infantile myasthenia |
c.1687C>T | p.Gln563Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial infantile myasthenia |
c.1775dup | p.Ala593fs | Pathogenic/Likely pathogenic | ★★☆☆ | Familial infantile myasthenia |
c.1850_1851del | p.Gly617fs | Pathogenic/Likely pathogenic | ★★☆☆ | Familial infantile myasthenia |
c.451C>T | p.Arg151Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome |
c.593G>A | p.Trp198Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial infantile myasthenia |
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 CHAT gene are associated with congenital myasthenic syndromes. These are a group of rare, inherited disorders characterised by impaired communication between nerves and muscles, leading to muscle weakness and fatigue. The specific symptoms and severity can vary significantly among affected individuals, depending on the nature of the genetic variant.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic CHAT 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 CHAT gene is part of several NHS Genomic Medicine Service approved panels in the UK. It is included in the Arthrogryposis, Congenital myasthenic syndrome, and Foetal anomalies panels, indicating its clinical relevance for these conditions within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the CHAT gene?
The CHAT gene provides instructions for making the enzyme choline acetyltransferase, which is crucial for producing acetylcholine. Acetylcholine is a neurotransmitter that enables communication between nerve cells and muscle cells, facilitating muscle movement.
How are conditions related to CHAT inherited?
Conditions associated with the CHAT gene are typically inherited in an autosomal recessive pattern. This means that an individual must inherit two altered copies of the gene, one from each parent, to develop the condition.
What are congenital myasthenic syndromes?
Congenital myasthenic syndromes are a group of rare, inherited disorders caused by disruptions in nerve-muscle communication. Variants in the CHAT gene can lead to these syndromes, resulting in symptoms like muscle weakness and fatigue.
References
- Barišić N, Chaouch A, Müller JS. Genetic heterogeneity and pathophysiological mechanisms in congenital myasthenic syndromes. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2011. PMID: 21498094
- Engel AG, Shen XM, Selcen D. What have we learned from the congenital myasthenic syndromes. Journal of molecular neuroscience : MN. 2010. PMID: 19688192
- Schara U, Christen HJ, Durmus H. Long-term follow-up in patients with congenital myasthenic syndrome due to CHAT mutations. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2010. PMID: 19900826