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CHRNA4 gene
URL of this page: https://medlineplus.gov/genetics/gene/chrna4/

CHRNA4 gene

cholinergic receptor nicotinic alpha 4 subunit

Normal Function

The CHRNA4 gene provides instructions for making one part (subunit) of a larger protein complex called a nicotinic acetylcholine receptor (nAChR). Each nAChR complex is made up of a combination of five subunits, usually two alpha (α) and three beta (β) subunits. Many different combinations are possible; the characteristics of each nAChR complex depend on its specific subunits. In the brain, the complex most commonly consists of two α4 subunits and three β2 subunits. The CHRNA4 gene is responsible for producing the α4 subunit.

In the brain, the nAChR complex plays an important role in chemical signaling between nerve cells (neurons). The nAChR acts as a channel, allowing charged atoms (ions), including calcium, sodium, and potassium, to cross the cell membrane. These channels open when they attach to a chemical messenger (neurotransmitter) called acetylcholine. The channels also open in response to nicotine, the addictive substance in tobacco. As these channels open, the increased flow of ions across the cell membrane alters the release of neurotransmitters.

Communication between neurons depends on neurotransmitters. The release and uptake of these chemicals are tightly regulated to ensure that signals are passed efficiently and accurately between neurons. Researchers believe that nAChR channels play an important role in controlling the normal release and uptake of neurotransmitters.

A wide range of brain functions depend on nAChR channels, including sleep and arousal, fatigue, anxiety, attention, pain perception, and memory. The channels are also active before birth, which suggests that they are involved in early brain development.

Health Conditions Related to Genetic Changes

Autosomal dominant sleep-related hypermotor epilepsy

Genetic changes that cause disease or that increase the risk of disease are sometimes called mutations or pathogenic variants. Pathogenic variants in the CHRNA4 gene have been identified in people with autosomal dominant sleep-related hypermotor epilepsy (ADSHE), a genetic form of epilepsy that is characterized by seizures that typically begin while a person is sleeping and involve some degree of muscle (motor) activity. The seizures may include repetitive, abnormal muscle movements; muscle stiffness; or abnormal body positioning. 

Pathogenic variants in the CHRNA4 gene can cause cells to produce subunits that make nAChR channels more sensitive to acetylcholine, which allows the channels to open more easily than usual. The resulting increase in ions crossing the cell membrane alters the release of neurotransmitters, which changes the signaling between neurons. As a result, it is likely that certain neurons are more active than usual, which triggers the abnormal brain activity associated with seizures. It is unclear why the seizures seen in people with ADSHE typically occur during sleep.

More About This Health Condition

Other disorders

Several common variations (polymorphisms) in the CHRNA4 gene likely contribute to a person's risk of nicotine dependence. Cigarettes and other forms of tobacco contain nicotine, a drug that interacts with nAChR channels in the brain to produce a feeling of heightened well-being and alertness. These feelings make nicotine highly addictive. 

Nicotine exerts its effects on the brain primarily by interacting with nAChR channels. Researchers have found several CHRNA4 polymorphisms that appear to lower a person’s risk of becoming addicted to nicotine. Many of these polymorphisms change a single protein building block (amino acid) in the α4 subunit of nAChR channels. These changes alter the structure of nAChR channels, which presumably affects the release and uptake of neurotransmitters in the brain.  

Research has shown that genetic factors play an important role in a person's vulnerability to nicotine dependence. However, like other forms of addiction, nicotine dependence is a complex behavior that is determined by multiple genetic and environmental factors. 

Other Names for This Gene

  • acetylcholine receptor, neuronal nicotonic, alpha-4 subunit
  • acetylcholine receptor, nicotinic, alpha 4 (neuronal)
  • BFNC
  • cholinergic receptor, neuronal nicotinic, alpha polypeptide 4
  • cholinergic receptor, nicotinic alpha 4
  • cholinergic receptor, nicotinic, alpha 4 (neuronal)
  • EBN
  • EBN1
  • NACHR
  • NACHRA4
  • NACRA4

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

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  • Hirose S, Iwata H, Akiyoshi H, Kobayashi K, Ito M, Wada K, Kaneko S, Mitsudome A. A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy. Neurology. 1999 Nov 10;53(8):1749-53. doi: 10.1212/wnl.53.8.1749. Citation on PubMed
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  • Kurahashi H, Hirose S. Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy. 2002 May 16 [updated 2023 Mar 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from http://www.ncbi.nlm.nih.gov/books/NBK1169/ Citation on PubMed
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  • Licchetta L, Pippucci T, Baldassari S, Minardi R, Provini F, Mostacci B, Plazzi G, Tinuper P, Bisulli F; Collaborative Group of Italian League Against Epilepsy (LICE) Genetic Study Group on SHE. Sleep-related hypermotor epilepsy (SHE): Contribution of known genes in 103 patients. Seizure. 2020 Jan;74:60-64. doi: 10.1016/j.seizure.2019.11.009. Epub 2019 Nov 23. Citation on PubMed
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  • Steinlein OK, Kaneko S, Hirose S. Nicotinic acetylcholine receptor mutations. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012. Available from http://www.ncbi.nlm.nih.gov/books/NBK98138/ Citation on PubMed
  • Steinlein OK, Mulley JC, Propping P, Wallace RH, Phillips HA, Sutherland GR, Scheffer IE, Berkovic SF. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 1995 Oct;11(2):201-3. doi: 10.1038/ng1095-201. Citation on PubMed
  • Tinuper P, Bisulli F, Cross JH, Hesdorffer D, Kahane P, Nobili L, Provini F, Scheffer IE, Tassi L, Vignatelli L, Bassetti C, Cirignotta F, Derry C, Gambardella A, Guerrini R, Halasz P, Licchetta L, Mahowald M, Manni R, Marini C, Mostacci B, Naldi I, Parrino L, Picard F, Pugliatti M, Ryvlin P, Vigevano F, Zucconi M, Berkovic S, Ottman R. Definition and diagnostic criteria of sleep-related hypermotor epilepsy. Neurology. 2016 May 10;86(19):1834-42. doi: 10.1212/WNL.0000000000002666. Epub 2016 Apr 15. Citation on PubMed

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