ATP1A3 explained

Sodium/potassium-transporting ATPase subunit alpha-3 is an enzyme that in humans is encoded by the ATP1A3 gene.^{[1] [2]}

Function

The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na⁺/K⁺-ATPases. Na⁺/K⁺-ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The catalytic subunit of Na⁺/K⁺-ATPase is encoded by multiple genes. This gene encodes an alpha 3 subunit.^[2] ATP1A3 is expressed early in human development, likely underlying pathophysiology related to several ATP1A3 related diseases.^[3]

Clinical significance

Disease causing variants of the ATP1A3 gene are known to cause a variety of movement disorders and epilepsies.^[4] The known associations include a variety of syndromes, in approximate order of presentation:

1. Malformation of Cortex Development, including polymicrogyria;
2. Developmental and epileptic encephalopathy 99 (DEE99);^[5]
3. Alternating hemiplegia of childhood 2 (AHC2);^[6]
4. Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss (CAPOS/CAOS syndrome);
5. Very early-onset schizophrenia;^[7]
6. Rapid-onset dystonia parkinsonism (RDP, also known as DYT12);
7. Fever-induced paroxysmal weakness and encephalopathy (FIPWE);
8. Recurrent episodes of cerebellar ataxia (RECA).

In mice, mutations in this gene are associated with epilepsy. By manipulating this gene in the offspring of such mice, epilepsy can be avoided.^[8]

Further reading

• Lingrel JB, Orlowski J, Shull MM, Price EM . Molecular genetics of Na,K-ATPase . Prog. Nucleic Acid Res. Mol. Biol. . 38 . 37–89 . 1990 . 2158121 . 10.1016/S0079-6603(08)60708-4 . 978-0-12-540038-1 . Progress in Nucleic Acid Research and Molecular Biology .
• Sverdlov ED, Monastyrskaia GS, Broude NE, ((Ushkarev IuA)), Melkov AM . The family of human Na⁺,K⁺-ATPase genes. Structure of the gene for isozyme alphaII . . 297 . 6 . 1488–94 . 1988 . 2834163 . The family of human Na⁺,⁺-ATPase genes. Structure of the gene for isozyme alphaII .
• Monastyrskaya GS, Broude NE, Melkov AM, Malyshev IV, Allikmets RL, Kostina MB, Dulubova IE . Family of human Na⁺, K⁺-ATPase genes. Structure of the gene for the catalytic subunit (alpha III-form) and its relationship with structural features of the protein . FEBS Lett. . 233 . 1 . 87–94 . 1988 . 2838329 . 10.1016/0014-5793(88)81361-9 . 1378625 . free .
• Yang-Feng TL, Schneider JW, Lindgren V, Shull MM, Benz EJ, Lingrel JB, Francke U . Chromosomal localization of human Na⁺, K⁺-ATPase alpha- and beta-subunit genes . Genomics . 2 . 2 . 128–38 . 1988 . 2842249 . 10.1016/0888-7543(88)90094-8 .
• Sverdlov ED, Broude NE, Sverdlov VE, Monastyrskaya GS, Grishin AV, Petrukhin KE, Akopyanz NS, Modyanov NN . Family of Na⁺,K⁺-ATPase genes. Intra-individual tissue-specific restriction fragment length polymorphism . FEBS Lett. . 221 . 1 . 129–33 . 1987 . 2887455 . 10.1016/0014-5793(87)80366-6 . 32756405 . free .
• Harley HG, Brook JD, Jackson CL, Glaser T, Walsh KV, Sarfarazi M, Kent R, Lager M, Koch M, Harper PS . Localization of a human Na⁺,K⁺-ATPase alpha subunit gene to chromosome 19q12----q13.2 and linkage to the myotonic dystrophy locus . Genomics . 3 . 4 . 380–4 . 1989 . 2907504 . 10.1016/0888-7543(88)90131-0 .
• Monastyrskaya GS, Broude NE, Allikmets RL, Melkov AM, Malyshev IV, Dulubova IE, Petrukhin KE . The family of human Na⁺,K⁺-ATPase genes. A partial nucleotide sequence related to the alpha-subunit . FEBS Lett. . 213 . 1 . 73–80 . 1987 . 3030810 . 10.1016/0014-5793(87)81467-9 . 35674738 . free .
• Shull MM, Lingrel JB . Multiple genes encode the human Na⁺,K⁺-ATPase catalytic subunit . Proc. Natl. Acad. Sci. U.S.A. . 84 . 12 . 4039–43 . 1987 . 3035563 . 305017 . 10.1073/pnas.84.12.4039 . 1987PNAS...84.4039S . free .
• Sverdlov ED, Monastyrskaya GS, Broude NE, Allikmets RL, Melkov AM, Malyshev IV, Dulobova IE, Petrukhin KE . The family of human Na⁺,K⁺-ATPase genes. No less than five genes and/or pseudogenes related to the alpha-subunit . FEBS Lett. . 217 . 2 . 275–8 . 1987 . 3036582 . 10.1016/0014-5793(87)80677-4 . 44449386 . free .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Kramer PL, Mineta M, Klein C, Schilling K, de Leon D, Farlow MR, Breakefield XO, Bressman SB, Dobyns WB, Ozelius LJ, Brashear A . Rapid-onset dystonia-parkinsonism: linkage to chromosome 19q13 . Ann. Neurol. . 46 . 2 . 176–82 . 1999 . 10443882 . 10.1002/1531-8249(199908)46:2<176::AID-ANA6>3.0.CO;2-2 . 10773650 .
• Esplin MS, Fausett MB, Faux DS, Graves SW . Changes in the isoforms of the sodium pump in the placenta and myometrium of women in labor . Am. J. Obstet. Gynecol. . 188 . 3 . 759–64 . 2003 . 12634653 . 10.1067/mob.[phone] .
• 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⁺/⁺-ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism . Neuron . 43 . 2 . 169–75 . 2004 . 15260953 . 10.1016/j.neuron.2004.06.028 . 15874616 . free .
• Benfante R, Antonini RA, Vaccari M, Flora A, Chen F, Clementi F, Fornasari D . The expression of the human neuronal α3 Na⁺,K⁺-ATPase subunit gene is regulated by the activity of the Sp1 and NF-Y transcription factors . Biochem. J. . 386 . Pt 1 . 63–72 . 2005 . 15462673 . 1134767 . 10.1042/BJ20041294 .
• Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration . Cell . 125 . 4 . 801–14 . 2006 . 16713569 . 10.1016/j.cell.2006.03.032 . 13709685 . free .

External links

• GeneReview/NCBI/NIH/UW entry on Rapid-Onset Dystonia Parkinsonism

Notes and References

1. 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) and mutations in the ATP1A3 gene . Brain . 130 . Pt 3 . 828–35 . Mar 2007 . 17282997 . 10.1093/brain/awl340 . free .
2. Web site: Entrez Gene: ATP1A3 ATPase, Na⁺/K⁺ transporting, alpha 3 polypeptide.
3. Smith RS, Florio M, Akula SK, Neil JE, Wang Y, Hill RS, Goldman M, Mullally CD, Reed N, Bello-Espinosa L, Flores-Sarnat L, Monteiro FP, Erasmo CB, Pinto e Vairo F, Morava E, Barkovich AJ, Gonzalez-Heydrich J, Brownstein CA, McCarroll SA, Walsh CA . 6 . Early role for a Na +,K + -ATPase (ATP1A3) in brain development . Proceedings of the National Academy of Sciences . 2021-06-22 . 118 . 25 . e2023333118 . 10.1073/pnas.2023333118 . 34161264 . 8237684 . 2021PNAS..11823333S . free .
4. Papandreou A, Danti FR, Spaull R, Leuzzi V, Mctague A, Kurian MA . The expanding spectrum of movement disorders in genetic epilepsies . Developmental Medicine and Child Neurology . 62 . 2 . 178–191 . February 2020 . 31784983 . 10.1111/dmcn.14407 . 208498567 .
5. Web site: UniProt . 2023-10-31 . www.uniprot.org.
6. https://www.uniprot.org/uniprotkb/P13637/entry#disease_variants
7. Smedemark-Margulies N, Brownstein CA, Vargas S, Tembulkar SK, Towne MC, Shi J, Gonzalez-Cuevas E, Liu KX, Bilguvar K, Kleiman RJ, Han MJ, Torres A, Berry GT, Yu TW, Beggs AH, Agrawal PB, Gonzalez-Heydrich J . A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia . Cold Spring Harbor Molecular Case Studies . 2 . 5 . a001008 . September 2016 . 27626066 . 5002930 . 10.1101/mcs.a001008 .
8. Clapcote SJ, Duffy S, Xie G, Kirshenbaum G, Bechard AR, Rodacker Schack V, Petersen J, Sinai L, Saab BJ, Lerch JP, Minassian BA, Ackerley CA, Sled JG, Cortez MA, Henderson JT, Vilsen B, Roder JC . Mutation I810N in the alpha3 isoform of Na⁺,K⁺-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS . Proc. Natl. Acad. Sci. U.S.A. . 106 . 33 . 14085–90 . August 2009 . 19666602 . 2729024 . 10.1073/pnas.0904817106 . 2009PNAS..10614085C . free .