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CACNA1A

Reviewed February 2014

What is the official name of the CACNA1A gene?

The official name of this gene is “calcium channel, voltage-dependent, P/Q type, alpha 1A subunit.”

CACNA1A is the gene's official symbol. The CACNA1A gene is also known by other names, listed below.

What is the normal function of the CACNA1A gene?

The CACNA1A gene belongs to a family of genes that provide instructions for making calcium channels. These channels, which transport positively charged calcium atoms (calcium ions) across cell membranes, play a key role in a cell's ability to generate and transmit electrical signals. Calcium ions are involved in many different cellular functions, including cell-to-cell communication, the tensing of muscle fibers (muscle contraction), and the regulation of certain genes.

The CACNA1A gene provides instructions for making one part (the alpha-1 subunit) of a calcium channel called CaV2.1. This subunit forms the hole (pore) through which calcium ions can flow. CaV2.1 channels play an essential role in communication between nerve cells (neurons) in the brain. These channels help control the release of neurotransmitters, which are chemicals that relay signals from one neuron to another. Researchers believe that CaV2.1 channels are also involved in the survival of neurons and the ability of these cells to change and adapt over time (plasticity).

Near one end of the CACNA1A gene, a segment of three DNA building blocks (nucleotides) is repeated multiple times. This sequence, which is written as CAG, is called a triplet or trinucleotide repeat. In most people, the number of CAG repeats in this gene ranges from 4 to 18.

Does the CACNA1A gene share characteristics with other genes?

The CACNA1A gene belongs to a family of genes called CACN (calcium channels).

A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genefamilies) in the Handbook.

How are changes in the CACNA1A gene related to health conditions?

episodic ataxia - caused by mutations in the CACNA1A gene

More than 50 mutations in the CACNA1A gene have been found to cause episodic ataxia type 2 (EA2), the most common form of episodic ataxia. In addition to problems with coordination and balance (ataxia), EA2 is associated with involuntary eye movements called nystagmus. The CACNA1A mutations responsible for EA2 reduce the production of functional CaV2.1 channels or prevent these channels from reaching the cell membrane, where they are needed to transport calcium ions. A decrease in the number of these channels reduces the total flow of calcium ions into neurons, which disrupts the release of neurotransmitters in the brain. Although changes in signaling between neurons underlie the episodes of uncoordinated movement seen in people with episodic ataxia, it is unclear how altered calcium ion transport causes the specific features of the condition.

familial hemiplegic migraine - caused by mutations in the CACNA1A gene

At least 20 mutations in the CACNA1A gene have been identified in people with familial hemiplegic migraine type 1 (FHM1). This condition is characterized by migraine headaches with a pattern of neurological symptoms known as aura. In FHM1, the aura includes temporary numbness or weakness on one side of the body (hemiparesis). Like EA2, FHM1 is commonly associated with ataxia and nystagmus. Most of the mutations that cause FHM1 change single protein building blocks (amino acids) in the CaV2.1 channel. The most common mutation, which has been found in more than a dozen affected families, replaces the amino acid threonine with the amino acid methionine at protein position 666 (written as Thr666Met or T666M).

The CACNA1A mutations responsible for familial hemiplegic migraine change the structure of the CaV2.1 channel. The altered channels open more easily than usual, which increases the inward flow of calcium ions. A greater influx of calcium ions through CaV2.1 channels increases the cell's release of neurotransmitters. The resulting changes in signaling between neurons lead to development of these severe headaches in people with familial hemiplegic migraine.

spinocerebellar ataxia type 6 - caused by mutations in the CACNA1A gene

Spinocerebellar ataxia type 6 (SCA6) is another disorder caused by CACNA1A gene mutations. The major features of this condition include progressive ataxia, nystagmus, and impaired speech (dysarthria), most often beginning in a person's forties or fifties. SCA6 results from an increased number of copies (expansion) of the CAG trinucleotide repeat in the CACNA1A gene. In people with this condition, the CAG segment is repeated from 20 to more than 30 times.

An increase in the length of the CAG segment leads to the production of an abnormally long version of the alpha-1 subunit. The abnormal subunit is found in the cell membrane as well as in the fluid inside cells (cytoplasm), where it clusters together and forms clumps (aggregates). The effect these aggregates have on cell functioning is unknown. The lack of normal calcium channels impairs the cells' ability to transport calcium ions. These changes alter the release of neurotransmitters in the brain and eventually lead to the death of neurons. Certain neurons called Purkinje cells seem to be particularly sensitive to a disruption in calcium transport. Purkinje cells are located in the part of the brain that coordinates movement (cerebellum). Over time, the loss of Purkinje cells and other cells of the cerebellum causes the movement problems characteristic of SCA6.

sporadic hemiplegic migraine - caused by mutations in the CACNA1A gene

At least nine mutations in the CACNA1A gene have been found to cause sporadic hemiplegic migraine. The signs and symptoms of this condition are identical to those of FHM1 (described above); however, sporadic hemiplegic migraine occurs in people with no family history of the condition. As in FHM1, sporadic hemiplegic migraine caused by CACNA1A gene mutations is commonly associated with ataxia and nystagmus in addition to migraine headaches and auras.

CACNA1A gene mutations that cause sporadic hemiplegic migraine change single amino acids in the CaV2.1 channel. Many of these mutations are also found in families with FHM1. The altered channels are more active than usual, which increases the release of neurotransmitters. The abnormal signaling between neurons caused by these changes lead to the headaches and auras characteristic of sporadic hemiplegic migraine.

Where is the CACNA1A gene located?

Cytogenetic Location: 19p13

Molecular Location on chromosome 19: base pairs 13,206,441 to 13,506,459

The CACNA1A gene is located on the short (p) arm of chromosome 19 at position 13.

The CACNA1A gene is located on the short (p) arm of chromosome 19 at position 13.

More precisely, the CACNA1A gene is located from base pair 13,206,441 to base pair 13,506,459 on chromosome 19.

See How do geneticists indicate the location of a gene? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation) in the Handbook.

Where can I find additional information about CACNA1A?

You and your healthcare professional may find the following resources about CACNA1A helpful.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

What other names do people use for the CACNA1A gene or gene products?

  • APCA
  • brain calcium channel 1
  • CAC1A_HUMAN
  • CACNL1A4
  • calcium channel, alpha 1A subunit
  • calcium channel, L type, alpha-1 polypeptide, isoform 4
  • CAV2.1
  • HPCA
  • SCA6
  • Voltage-gated calcium channel subunit alpha Cav2.1

See How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What glossary definitions help with understanding CACNA1A?

acids ; amino acid ; ataxia ; aura ; calcium ; cell ; cell membrane ; cerebellum ; channel ; contraction ; cytoplasm ; depression ; DNA ; dysarthria ; familial ; family history ; gene ; hemiparesis ; hemiplegic ; involuntary ; ions ; ion transport ; methionine ; migraine ; mutation ; neurological ; neuron ; neurotransmitters ; nystagmus ; plasticity ; protein ; Purkinje cells ; sporadic ; subunit ; threonine ; trinucleotide repeat ; voltage

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • de Vries B, Freilinger T, Vanmolkot KR, Koenderink JB, Stam AH, Terwindt GM, Babini E, van den Boogerd EH, van den Heuvel JJ, Frants RR, Haan J, Pusch M, van den Maagdenberg AM, Ferrari MD, Dichgans M. Systematic analysis of three FHM genes in 39 sporadic patients with hemiplegic migraine. Neurology. 2007 Dec 4;69(23):2170-6. (http://www.ncbi.nlm.nih.gov/pubmed/18056581?dopt=Abstract)
  • Jeng CJ, Sun MC, Chen YW, Tang CY. Dominant-negative effects of episodic ataxia type 2 mutations involve disruption of membrane trafficking of human P/Q-type Ca2+ channels. J Cell Physiol. 2008 Feb;214(2):422-33. (http://www.ncbi.nlm.nih.gov/pubmed/17654512?dopt=Abstract)
  • Jen JC, Graves TD, Hess EJ, Hanna MG, Griggs RC, Baloh RW; CINCH investigators. Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain. 2007 Oct;130(Pt 10):2484-93. Epub 2007 Jun 15. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17575281?dopt=Abstract)
  • Kordasiewicz HB, Gomez CM. Molecular pathogenesis of spinocerebellar ataxia type 6. Neurotherapeutics. 2007 Apr;4(2):285-94. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17395139?dopt=Abstract)
  • Kors EE, Haan J, Giffin NJ, Pazdera L, Schnittger C, Lennox GG, Terwindt GM, Vermeulen FL, Van den Maagdenberg AM, Frants RR, Ferrari MD. Expanding the phenotypic spectrum of the CACNA1A gene T666M mutation: a description of 5 families with familial hemiplegic migraine. Arch Neurol. 2003 May;60(5):684-8. (http://www.ncbi.nlm.nih.gov/pubmed/12756131?dopt=Abstract)
  • NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/773)
  • Pietrobon D. Familial hemiplegic migraine. Neurotherapeutics. 2007 Apr;4(2):274-84. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17395138?dopt=Abstract)
  • Rajakulendran S, Schorge S, Kullmann DM, Hanna MG. Dysfunction of the Ca(V)2.1 calcium channel in cerebellar ataxias. F1000 Biol Rep. 2010 Jan 18;2. pii: 4. doi: 10.3410/B2-4. (http://www.ncbi.nlm.nih.gov/pubmed/20948794?dopt=Abstract)
  • Riant F, Ducros A, Ploton C, Barbance C, Depienne C, Tournier-Lasserve E. De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine. Neurology. 2010 Sep 14;75(11):967-72. doi: 10.1212/WNL.0b013e3181f25e8f. (http://www.ncbi.nlm.nih.gov/pubmed/20837964?dopt=Abstract)
  • Strupp M, Zwergal A, Brandt T. Episodic ataxia type 2. Neurotherapeutics. 2007 Apr;4(2):267-73. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17395137?dopt=Abstract)
  • Terwindt G, Kors E, Haan J, Vermeulen F, Van den Maagdenberg A, Frants R, Ferrari M. Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine. Arch Neurol. 2002 Jun;59(6):1016-8. Review. (http://www.ncbi.nlm.nih.gov/pubmed/12056940?dopt=Abstract)
  • Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, Fletcher C, Pietrobon D. Familial hemiplegic migraine mutations increase Ca(2+) influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons. Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13284-9. Epub 2002 Sep 16. (http://www.ncbi.nlm.nih.gov/pubmed/12235360?dopt=Abstract)
  • Wan J, Khanna R, Sandusky M, Papazian DM, Jen JC, Baloh RW. CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics. Neurology. 2005 Jun 28;64(12):2090-7. (http://www.ncbi.nlm.nih.gov/pubmed/15985579?dopt=Abstract)
  • Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet. 1997 Jan;15(1):62-9. (http://www.ncbi.nlm.nih.gov/pubmed/8988170?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: February 2014
Published: April 17, 2014