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Journal of Neurology

, Volume 267, Issue 1, pp 203–213 | Cite as

ATP8A2-related disorders as recessive cerebellar ataxia

  • Claire GuissartEmail author
  • Alexander N. Harrison
  • Mehdi Benkirane
  • Ibrahim Oncel
  • Elif Acar Arslan
  • Anna K . Chassevent
  • Kristin Baraῆano
  • Lise Larrieu
  • Maria Iascone
  • Romano Tenconi
  • Mireille Claustres
  • Nesibe Eroglu-Ertugrul
  • Patrick Calvas
  • Haluk Topaloglu
  • Robert S. Molday
  • Michel Koenig
Original Communication
  • 143 Downloads

Abstract

ATP8A2-related disorders are autosomal recessive conditions that associate encephalopathy with or without hypotonia, psychomotor delay, abnormal movements, chorea, tremor, optic atrophy and cerebellar atrophy (CARMQ4). Through a multi-centric collaboration, we identified six point mutations (one splice site and five missense mutations) involving ATP8A2 in six individuals from five families. Two patients from one family with the homozygous p.Gly585Val mutation had a milder presentation without encephalopathy. Expression and functional studies of the missense mutations demonstrated that protein levels of four of the five missense variants were very low and lacked phosphatidylserine-activated ATPase activity. One variant p.Ile215Leu, however, expressed at normal levels and displayed phospholipid-activated ATPase activity similar to the non-mutated protein. We therefore expand for the first time the phenotype related to ATP8A2 mutations to less severe forms characterized by cerebellar ataxia without encephalopathy and suggest that ATP8A2 should be analyzed for all cases of syndromic or non-syndromic recessive or sporadic ataxia.

Keywords

Ataxia ATP8A2 CAMRQ P4-ATPase Psychomotor delay 

Notes

Acknowledgements

The authors thank the families and patients described herein for their participation in this study. The corresponding author had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This study was supported by funds from the Agence Nationale pour la Recherche (ANR)/E-rare Joint Trans-national Call (JTC) 2011 ‘Euro-SCAR’ (2011-RARE-004–01 to M.K.) and the Canadian Institutes of Health Research grant (PJT 148649 to RSM).

Author contributions

CG and MK: conception and design of the study; AH, AC, CG, EAA, HT, IO, KB, LL, MB, MI, MK, NEE, PC, RSM, RT: contributed to acquisition, analysis, and interpretation of data; CG, MB, MK and RSM: contributed to drafting the manuscript or figures; AC, CG, EAA, HT, IO, KB, LL, MB, MC, MI, MK, NEE, PC, RSM, RT: contributed to critical revision of the manuscript, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflicts of interest.

Supplementary material

415_2019_9579_MOESM1_ESM.xlsx (20 kb)
Supplementary file1 (XLSX 20 kb)
415_2019_9579_MOESM2_ESM.docx (14 kb)
Supplementary file2 (DOCX 13 kb)

References

  1. 1.
    Tan U (2006) A new syndrome with quadrupedal gait, primitive speech, and severe mental retardation as a live model for human evolution. Int J Neurosci 116:361–369.  https://doi.org/10.1080/00207450500455330 CrossRefPubMedGoogle Scholar
  2. 2.
    Schlotawa L, Hotz A, Zeschnigk C et al (2013) Cerebellar ataxia, mental retardation and dysequilibrium syndrome 1 (CAMRQ1) caused by an unusual constellation of VLDLR mutation. J Neurol 260:1678–1680.  https://doi.org/10.1007/s00415-013-6941-z CrossRefPubMedGoogle Scholar
  3. 3.
    Doldur-Balli F, Ozel MN, Gulsuner S et al (2015) Characterization of a novel zebrafish (Danio rerio) gene, wdr81, associated with cerebellar ataxia, mental retardation and dysequilibrium syndrome (CAMRQ). BMC Neurosci 16:96.  https://doi.org/10.1186/s12868-015-0229-4 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Türkmen S, Guo G, Garshasbi M et al (2009) CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait. PLoS Genet 5:e1000487.  https://doi.org/10.1371/journal.pgen.1000487 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Onat OE, Gulsuner S, Bilguvar K et al (2013) Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion. Eur J Hum Genet 21:281–285.  https://doi.org/10.1038/ejhg.2012.170 CrossRefPubMedGoogle Scholar
  6. 6.
    Martín-Hernández E, Rodríguez-García ME, Camacho A et al (2016) New ATP8A2 gene mutations associated with a novel syndrome: encephalopathy, intellectual disability, severe hypotonia, chorea and optic atrophy. Neurogenetics 17:259–263.  https://doi.org/10.1007/s10048-016-0496-y CrossRefPubMedGoogle Scholar
  7. 7.
    McMillan HJ, Telegrafi A, Singleton A et al (2018) Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy. Orphanet J Rare Dis 13:86.  https://doi.org/10.1186/s13023-018-0825-3 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Alsahli S, Alrifai MT, Al Tala S et al (2018) Further delineation of the clinical phenotype of cerebellar ataxia, mental retardation, and disequilibrium syndrome type 4. J Cent Nerv Syst Dis 10:1179573518759682.  https://doi.org/10.1177/1179573518759682 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Guissart C, Li X, Leheup B et al (2015) Mutation of SLC9A1, encoding the major Na+/H+ exchanger, causes ataxia-deafness Lichtenstein–Knorr syndrome. Hum Mol Genet 24:463–470.  https://doi.org/10.1093/hmg/ddu461 CrossRefPubMedGoogle Scholar
  10. 10.
    Marelli C, Guissart C, Hubsch C et al (2016) Mini-exome coupled to read-depth based copy number variation analysis in patients with inherited ataxias. Hum Mutat 37:1340–1353.  https://doi.org/10.1002/humu.23063 CrossRefPubMedGoogle Scholar
  11. 11.
    Platzer K, Sticht H, Edwards SL et al (2019) De novo variants in MAPK8IP3 cause intellectual disability with variable brain anomalies. Am J Hum Genet 104:203–212.  https://doi.org/10.1016/j.ajhg.2018.12.008 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lee S, Uchida Y, Wang J et al (2015) Transport through recycling endosomes requires EHD1 recruitment by a phosphatidylserine translocase. EMBO J 34:669–688.  https://doi.org/10.15252/embj.201489703 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Coleman JA, Molday RS (2011) Critical role of the β-subunit CDC50A in the stable expression, assembly, subcellular localization, and lipid transport activity of the P 4-ATPase ATP8A2. J Biol Chem 286:17205–17216.  https://doi.org/10.1074/jbc.M111.229419 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Coleman JA, Kwok MCM, Molday RS (2009) Localization, purification, and functional reconstitution of the P4-ATPase Atp8a2, a phosphatidylserine flippase in photoreceptor disc membranes. J Biol Chem 284:32670–32679.  https://doi.org/10.1074/jbc.M109.047415 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Cacciagli P, Haddad M-R, Mignon-Ravix C et al (2010) Disruption of the ATP8A2 gene in a patient with a t(10;13) de novo balanced translocation and a severe neurological phenotype. Eur J Hum Genet 18:1360–1363.  https://doi.org/10.1038/ejhg.2010.126 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    De Simone R, Ajmone-Cat MA, Minghetti L (2004) Atypical antiinflammatory activation of microglia induced by apoptotic neurons: possible role of phosphatidylserine-phosphatidylserine receptor interaction. Mol Neurobiol 29:197–212.  https://doi.org/10.1385/MN:29:2:197 CrossRefPubMedGoogle Scholar
  17. 17.
    Wang J, Molday LL, Hii T et al (2018) Proteomic analysis and functional characterization of P4-ATPase phospholipid flippases from murine tissues. Sci Rep 8:10795.  https://doi.org/10.1038/s41598-018-29108-z CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Vestergaard AL, Coleman JA, Lemmin T et al (2014) Critical roles of isoleucine-364 and adjacent residues in a hydrophobic gate control of phospholipid transport by the mammalian P4-ATPase ATP8A2. Proc Natl Acad Sci U S A 111:E1334–E1343.  https://doi.org/10.1073/pnas.1321165111 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Beaudin M, Matilla-Dueñas A, Soong B-W et al (2019) The classification of autosomal recessive cerebellar ataxias: a consensus statement from the society for research on the cerebellum and ataxias task force. Cerebellum.  https://doi.org/10.1007/s12311-019-01052-2 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Rossi M, Anheim M, Durr A et al (2018) The genetic nomenclature of recessive cerebellar ataxias. Mov Disord 33:1056–1076.  https://doi.org/10.1002/mds.27415 CrossRefPubMedGoogle Scholar
  21. 21.
    Anheim M, Tranchant C, Koenig M (2012) The autosomal recessive cerebellar ataxias. N Engl J Med 366:636–646.  https://doi.org/10.1056/NEJMra1006610 CrossRefPubMedGoogle Scholar
  22. 22.
    Renaud M, Guissart C, Mallaret M et al (2016) Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia. J Neurol 263:1552–1558.  https://doi.org/10.1007/s00415-016-8167-3 CrossRefPubMedGoogle Scholar
  23. 23.
    Guissart C, Drouot N, Oncel I et al (2016) Genes for spinocerebellar ataxia with blindness and deafness (SCABD/SCAR3, MIM# 271250 and SCABD2). Eur J Hum Genet 24:1154–1159.  https://doi.org/10.1038/ejhg.2015.259 CrossRefPubMedGoogle Scholar
  24. 24.
    Carré G, Marelli C, Anheim M et al (2017) Xeroderma pigmentosum complementation group F: a rare cause of cerebellar ataxia with chorea. J Neurol Sci 376:198–201.  https://doi.org/10.1016/j.jns.2017.03.021 CrossRefPubMedGoogle Scholar
  25. 25.
    Marelli C, Hamel C, Quiles M et al (2018) ACO2 mutations: a novel phenotype associating severe optic atrophy and spastic paraplegia. Neurol Genet 4:e225.  https://doi.org/10.1212/NXG.0000000000000225 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Claire Guissart
    • 1
    Email author
  • Alexander N. Harrison
    • 2
  • Mehdi Benkirane
    • 1
  • Ibrahim Oncel
    • 3
  • Elif Acar Arslan
    • 4
  • Anna K . Chassevent
    • 5
  • Kristin Baraῆano
    • 5
  • Lise Larrieu
    • 1
  • Maria Iascone
    • 6
  • Romano Tenconi
    • 7
  • Mireille Claustres
    • 1
  • Nesibe Eroglu-Ertugrul
    • 3
  • Patrick Calvas
    • 8
  • Haluk Topaloglu
    • 3
  • Robert S. Molday
    • 2
  • Michel Koenig
    • 1
  1. 1.Laboratoire de Génétique de Maladies Rares EA7402, Institut Universitaire de Recherche CliniqueUniversité de Montpellier, CHU MontpellierMontpellierFrance
  2. 2.Biochemistry & Molecular BiologyUniversity of British ColumbiaVancouverCanada
  3. 3.Department of Pediatric NeurologyHacettepe University Children’s HospitalAnkaraTurkey
  4. 4.Department of Pediatric NeurologyKaradeniz Technical University School of MedicineTrabzonTurkey
  5. 5.Department of NeurogeneticsKennedy Krieger InstituteBaltimoreUSA
  6. 6.Laboratory of Genetic MedicineASST Papa Giovanni XXIIIBergamoItaly
  7. 7.Dipartimento di Pediatria, Genetica ClinicaUniversità di PadovaPadovaItaly
  8. 8.Department of Clinical GeneticsPurpan University HospitalToulouseFrance

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