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    ATP1A3 Gene

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    Submitted by: Vicky Zhou
    (This entry belongs to Entry Collection "MedlinePlus ")

    Definition

    ATPase Na+/K+ transporting subunit alpha 3

    1. Normal Function

    The ATP1A3 gene provides instructions for making one part (the alpha-3 subunit) of a protein known as Na+/K+ ATPase or the sodium pump. This protein uses energy from a molecule called adenosine triphosphate (ATP) to transport charged atoms (ions) into and out of cells. Specifically, it pumps sodium ions (Na+) out of cells and potassium ions (K+) into cells.

    Na+/K+ ATPases that include the alpha-3 subunit are primarily found in nerve cells (neurons) in the brain and are critical for their normal function. The movement of sodium and potassium ions helps regulate the electrical activity of these cells and plays an important role in the signaling process that controls muscle movement. The activity of Na+/K+ ATPase also helps regulate cell size (volume).

    Additionally, Na+/K+ ATPase helps regulate a process called neurotransmitter reuptake. Neurotransmitters are chemicals that transmit signals from one neuron to another. After a neurotransmitter has had its effect, it must be removed quickly from the space between the neurons. The reuptake of neurotransmitters is carefully controlled to ensure that signals are sent and received accurately throughout the nervous system.

    2. Health Conditions Related to Genetic Changes

    2.1. Alternating Hemiplegia of Childhood

    Mutations in the ATP1A3 gene are the primary cause of a neurological condition called alternating hemiplegia of childhood; at least 25 ATP1A3 gene mutations have been found in affected individuals. This condition is characterized by recurrent episodes of temporary paralysis, often affecting one side of the body (hemiplegia). During some episodes, the paralysis alternates from one side to the other or affects both sides of the body at the same time.

    Most ATP1A3 gene mutations associated with alternating hemiplegia of childhood change single protein building blocks (amino acids) in the alpha-3 subunit of Na+/K+ ATPase. These genetic changes appear to impair the pump's ability to transport ions, although it is unclear how the mutations lead to the specific features of alternating hemiplegia of childhood.

    2.2. Rapid-Onset Dystonia Parkinsonism

    At least nine mutations in the ATP1A3 gene have been identified in individuals and families with rapid-onset dystonia parkinsonism. Most of these mutations change single amino acids in the alpha-3 subunit of Na+/K+ ATPase. Changes in the protein's structure can reduce its activity or make it unstable. Studies suggest that the defective Na+/K+ ATPase is unable to transport sodium ions normally, which disrupts the electrical activity of neurons in the brain. However, it is unclear how a malfunctioning Na+/K+ ATPase causes the movement abnormalities characteristic of rapid-onset dystonia parkinsonism.

    3. Other Names for This Gene

    • AT1A3_HUMAN
    • ATPase, Na+/K+ transporting, alpha 3 polypeptide
    • DYT12
    • MGC13276
    • Na+/K+ -ATPase alpha 3 subunit
    • Na+/K+ ATPase 3
    • RDP
    • sodium pump 3
    • sodium-potassium-ATPase, alpha 3 polypeptide
    • sodium/potassium-transporting ATPase alpha-3 chain

    This entry is adapted from https://medlineplus.gov/genetics/gene/atp1a3

    References

    1. Blanco-Arias P, Einholm AP, Mamsa H, Concheiro C, Gutiérrez-de-Terán H, RomeroJ, Toustrup-Jensen MS, Carracedo A, Jen JC, Vilsen B, Sobrido MJ. A C-terminalmutation of ATP1A3 underscores the crucial role of sodium affinity in thepathophysiology of rapid-onset dystonia-parkinsonism. Hum Mol Genet. 2009 Jul1;18(13):2370-7. doi: 10.1093/hmg/ddp170.
    2. Brashear A, Dobyns WB, de Carvalho Aguiar P, Borg M, Frijns CJ, Gollamudi S,Green A, Guimaraes J, Haake BC, Klein C, Linazasoro G, Münchau A, Raymond D,Riley D, Saunders-Pullman R, Tijssen MA, Webb D, Zaremba J, Bressman SB, Ozelius LJ. The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) andmutations in the ATP1A3 gene. Brain. 2007 Mar;130(Pt 3):828-35.
    3. Brashear A, Sweadner KJ, Cook JF, Swoboda KJ, Ozelius L. ATP1A3-RelatedNeurologic Disorders. 2008 Feb 7 [updated 2018 Feb 22]. In: Adam MP, Ardinger HH,Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews®[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Availablefrom http://www.ncbi.nlm.nih.gov/books/NBK1115/
    4. de Carvalho Aguiar P, Sweadner KJ, Penniston JT, Zaremba J, Liu L, Caton M,Linazasoro G, Borg M, Tijssen MA, Bressman SB, Dobyns WB, Brashear A, Ozelius LJ.Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated withrapid-onset dystonia parkinsonism. Neuron. 2004 Jul 22;43(2):169-75.
    5. Heinzen EL, Swoboda KJ, Hitomi Y, Gurrieri F, Nicole S, de Vries B, TizianoFD, Fontaine B, Walley NM, Heavin S, Panagiotakaki E; European AlternatingHemiplegia of Childhood (AHC) Genetics Consortium; Biobanca e Registro Clinicoper l'Emiplegia Alternante (I.B.AHC) Consortium; European Network for Research onAlternating Hemiplegia (ENRAH) for Small and Medium-sized Enterpriese (SMEs)Consortium, Fiori S, Abiusi E, Di Pietro L, Sweney MT, Newcomb TM, Viollet L,Huff C, Jorde LB, Reyna SP, Murphy KJ, Shianna KV, Gumbs CE, Little L, Silver K, Ptáček LJ, Haan J, Ferrari MD, Bye AM, Herkes GK, Whitelaw CM, Webb D, Lynch BJ, Uldall P, King MD, Scheffer IE, Neri G, Arzimanoglou A, van den Maagdenberg AM,Sisodiya SM, Mikati MA, Goldstein DB. De novo mutations in ATP1A3 causealternating hemiplegia of childhood. Nat Genet. 2012 Sep;44(9):1030-4. doi:10.1038/ng.2358.
    6. Kamm C, Fogel W, Wächter T, Schweitzer K, Berg D, Kruger R, Freudenstein D,Gasser T. Novel ATP1A3 mutation in a sporadic RDP patient with minimal benefitfrom deep brain stimulation. Neurology. 2008 Apr 15;70(16 Pt 2):1501-3. doi:10.1212/01.wnl.0000310431.41036.e0.
    7. Rodacker V, Toustrup-Jensen M, Vilsen B. Mutations Phe785Leu and Thr618Met in Na+,K+-ATPase, associated with familial rapid-onset dystonia parkinsonism,interfere with Na+ interaction by distinct mechanisms. J Biol Chem. 2006 Jul7;281(27):18539-48.
    8. Rosewich H, Thiele H, Ohlenbusch A, Maschke U, Altmüller J, Frommolt P, ZirnB, Ebinger F, Siemes H, Nürnberg P, Brockmann K, Gärtner J. Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: awhole-exome sequencing gene-identification study. Lancet Neurol. 2012Sep;11(9):764-73. doi: 10.1016/S1474-4422(12)70182-5.
    9. Zanotti-Fregonara P, Vidailhet M, Kas A, Ozelius LJ, Clot F, Hindié E, Ravasi L, Devaux JY, Roze E. [123I]-FP-CIT and [99mTc]-HMPAO single photon emissioncomputed tomography in a new sporadic case of rapid-onset dystonia-parkinsonism. J Neurol Sci. 2008 Oct 15;273(1-2):148-51. doi: 10.1016/j.jns.2008.06.033.
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