Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Rare autosomal copy number variations in early-onset familial Alzheimer’s disease

Molecular Psychiatry volume 19, pages 676–681 (2014)Cite this article

Subjects

Abstract

Over 200 rare and fully penetrant pathogenic mutations in amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) cause a subset of early-onset familial Alzheimer’s disease (EO-FAD). Of these, 21 cases of EO-FAD families carrying unique APP locus duplications remain the only pathogenic copy number variations (CNVs) identified to date in Alzheimer’s disease (AD). Using high-density DNA microarrays, we performed a comprehensive genome-wide analysis for the presence of rare CNVs in 261 EO-FAD and early/mixed-onset pedigrees. Our analysis revealed 10 novel private CNVs in 10 EO-FAD families overlapping a set of genes that includes: A2BP1, ABAT, CDH2, CRMP1, DMRT1, EPHA5, EPHA6, ERMP1, EVC, EVC2, FLJ35024 and VLDLR. In addition, CNVs encompassing two known frontotemporal dementia genes, CHMP2B and MAPT were found. To our knowledge, this is the first study reporting rare gene-rich CNVs in EO-FAD and early/mixed-onset AD that are likely to underlie pathogenicity in familial AD and perhaps related dementias.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Tanzi RE, Bertram L . Twenty years of the Alzheimer's disease amyloid hypothesis: A genetic perspective. Cell 2005; 120: 545–555.

    Article  CAS  PubMed  Google Scholar 

  2. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 2006; 63: 168–174.

    Article  PubMed  Google Scholar 

  3. Hooli BV, Tanzi RE . A current view of Alzheimer's disease. F1000 Biol Rep 2009; 1.

  4. Bertram L, Lill CM, Tanzi RE . The genetics of Alzheimer disease: back to the future. Neuron 2010; 68: 270–281.

    Article  CAS  PubMed  Google Scholar 

  5. Bertram L, Tanzi RE . The genetics of Alzheimer's disease. Prog Mol Biol Transl Sci 2012; 107: 79–100.

    Article  CAS  PubMed  Google Scholar 

  6. Feuk L, Carson AR, Scherer SW . Structural variation in the human genome. Nat Rev Genet 2006; 7: 85–97.

    Article  CAS  PubMed  Google Scholar 

  7. Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, Thorne N et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 2007; 315: 848–853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Varki A, Geschwind DH, Eichler EE . Explaining human uniqueness: genome interactions with environment, behaviour and culture. Nat Rev Genet 2008; 9: 749–763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T et al. Strong association of de novo copy number mutations with autism. Science 2007; 316: 445–449.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Levy D, Ronemus M, Yamrom B, Lee YH, Leotta A, Kendall J et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 2011; 70: 886–897.

    Article  CAS  PubMed  Google Scholar 

  11. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 2011; 70: 863–885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Vacic V, McCarthy S, Malhotra D, Murray F, Chou HH, Peoples A et al. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature 2011; 471: 499–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bassett AS, Scherer SW, Brzustowicz LM . Copy number variations in schizophrenia: Critical review and new perspectives on concepts of genetics and disease. Am J Psychiatry 2010; 167: 899–914.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, Catano G et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 2005; 307: 1434–1440.

    Article  CAS  PubMed  Google Scholar 

  15. Townson JR, Barcellos LF, Nibbs RJ . Gene copy number regulates the production of the human chemokine CCL3-L1. Eur J Immunol 2002; 32: 3016–3026.

    Article  CAS  PubMed  Google Scholar 

  16. Lee C, Scherer SW . The clinical context of copy number variation in the human genome. Expert Rev Mol Med 2010; 12: e8.

    Article  PubMed  Google Scholar 

  17. Girirajan S, Eichler EE . Phenotypic variability and genetic susceptibility to genomic disorders. Hum Mol Genet 2010; 19: R176–R187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ionita-Laza I, Rogers AJ, Lange C, Raby BA, Lee C . Genetic association analysis of copy-number variation (CNV) in human disease pathogenesis. Genomics 2009; 93: 22–26.

    Article  CAS  PubMed  Google Scholar 

  19. Pagnamenta AT, Holt R, Yusuf M, Pinto D, Wing K, Betancur C et al. A family with autism and rare copy number variants disrupting the Duchenne/Becker muscular dystrophy gene DMD and TRPM3. J Neurodev Disord 2011; 3: 124–131.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Chartier-Harlin MC, Kachergus J, Roumier C, Mouroux V, Douay X, Lincoln S et al. Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 2004; 364: 1167–1169.

    Article  CAS  PubMed  Google Scholar 

  21. Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 2006; 38: 24–26.

    Article  CAS  PubMed  Google Scholar 

  22. Bertram L, Schjeide BM, Hooli B, Mullin K, Hiltunen M, Soininen H et al. No association between CALHM1 and Alzheimer's disease risk. Cell 2008; 135: 993–994, author reply 4-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ku CS, Pawitan Y, Sim X, Ong RT, Seielstad M, Lee EJ et al. Genomic copy number variations in three Southeast Asian populations. Hum Mutat 2010; 31: 851–857.

    Article  CAS  PubMed  Google Scholar 

  24. de Andrade M, Atkinson EJ, Bamlet WR, Matsumoto ME, Maharjan S, Slager SL et al. Evaluating the influence of quality control decisions and software algorithms on SNP calling for the affymetrix 6.0 SNP array platform. Hum Hered 2011; 71: 221–233.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Wang K, Li M, Hadley D, Liu R, Glessner J, Grant SF et al. PennCNV: An integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res 2007; 17: 1665–1674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Database of Genomic Variants [database on the Internet] 2011 Available from http://projects.tcag.ca/variation/project.html.

  27. Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y et al. Detection of large-scale variation in the human genome. Nat Genet 2004; 36: 949–951.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang J, Feuk L, Duggan GE, Khaja R, Scherer SW . Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome. Cytogenet Genome Res 2006; 115: 205–214.

    Article  CAS  PubMed  Google Scholar 

  29. Maiti S, Kumar KH, Castellani CA, O'Reilly R, Singh SM . Ontogenetic de novo copy number variations (CNVs) as a source of genetic individuality: Studies on two families with MZD twins for schizophrenia. PLoS One 2011; 6: e17125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. UCSC Genome Bioinformatics: FAQ [database on the Internet] 2012 Available from http://genome.ucsc.edu/FAQ/FAQformat.html#format1.

  31. Qin J, Jones RC, Ramakrishnan R . Studying copy number variations using a nanofluidic platform. Nucleic Acids Res 2008; 36: e116.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Mohapatra G, Moore DH, Kim DH, Grewal L, Hyun WC, Waldman FM et al. Analyses of brain tumor cell lines confirm a simple model of relationships among fluorescence in situ hybridization, DNA index, and comparative genomic hybridization. Genes Chromosomes Cancer 1997; 20: 311–319.

    Article  CAS  PubMed  Google Scholar 

  33. Pang AW, MacDonald JR, Pinto D, Wei J, Rafiq MA, Conrad DF et al. Towards a comprehensive structural variation map of an individual human genome. Genome Biol 2010; 11: R52.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hooli BV, Mohapatra G, Mattheisen M, Parrado AR, Roehr JT, Shen Y et al. Role of common and rare APP DNA sequence variants in Alzheimer disease. Neurology 2012; 78: 1250–1257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Alzheimer Disease & Frontotemporal Dementia Mutation Database [database on the Internet] 1998 cited 21 March 2011.

  36. Kauwe JS, Jacquart S, Chakraverty S, Wang J, Mayo K, Fagan AM et al. Extreme cerebrospinal fluid amyloid beta levels identify family with late-onset Alzheimer's disease presenilin 1 mutation. Ann Neurol 2007; 61: 446–453.

    Article  CAS  PubMed  Google Scholar 

  37. Akiyama M, Ishida N, Ogawa T, Yogo K, Takeya T . Molecular cloning and functional analysis of a novel Cx43 partner protein CIP150. Biochem Biophys Res Commun 2005; 335: 1264–1271.

    Article  CAS  PubMed  Google Scholar 

  38. Farahani R, Pina-Benabou MH, Kyrozis A, Siddiq A, Barradas PC, Chiu FC et al. Alterations in metabolism and gap junction expression may determine the role of astrocytes as "good samaritans" or executioners. Glia 2005; 50: 351–361.

    Article  PubMed  Google Scholar 

  39. Perez Velazquez JL, Frantseva MV, Naus CC . Gap junctions and neuronal injury: Protectants or executioners? Neuroscientist 2003; 9: 5–9.

    Article  CAS  PubMed  Google Scholar 

  40. Martin B, Brenneman R, Becker KG, Gucek M, Cole RN, Maudsley S . iTRAQ analysis of complex proteome alterations in 3xTgAD Alzheimer's mice: understanding the interface between physiology and disease. PLoS One 2008; 3: e2750.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Bergren SK, Rutter ED, Kearney JA . Fine mapping of an epilepsy modifier gene on mouse Chromosome 19. Mamm Genome 2009; 20: 359–366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sund KL, Roelker S, Ramachandran V, Durbin L, Benson DW . Analysis of Ellis van Creveld syndrome gene products: implications for cardiovascular development and disease. Hum Mol Genet 2009; 18: 1813–1824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Schmidt EF, Strittmatter SM . The CRMP family of proteins and their role in Sema3A signaling. Adv Exp Med Biol 2007; 600: 1–11.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Good PF, Alapat D, Hsu A, Chu C, Perl D, Wen X et al. A role for semaphorin 3A signaling in the degeneration of hippocampal neurons during Alzheimer's disease. J Neurochem 2004; 91: 716–736.

    Article  CAS  PubMed  Google Scholar 

  45. Yamashita N, Uchida Y, Ohshima T, Hirai S, Nakamura F, Taniguchi M et al. Collapsin response mediator protein 1 mediates reelin signaling in cortical neuronal migration. J Neurosci 2006; 26: 13357–13362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mukherjee J, DeSouza LV, Micallef J, Karim Z, Croul S, Siu KW et al. Loss of collapsin response mediator Protein1, as detected by iTRAQ analysis, promotes invasion of human gliomas expressing mutant EGFRvIII. Cancer Res 2009; 69: 8545–8554.

    Article  CAS  PubMed  Google Scholar 

  47. Kurnellas MP, Li H, Jain MR, Giraud SN, Nicot AB, Ratnayake A et al. Reduced expression of plasma membrane calcium ATPase 2 and collapsin response mediator protein 1 promotes death of spinal cord neurons. Cell Death Differ 2010; 17: 1501–1510.

    Article  CAS  PubMed  Google Scholar 

  48. Cole AR, Noble W, van Aalten L, Plattner F, Meimaridou R, Hogan D et al. Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer's disease progression. J Neurochem 2007; 103: 1132–1144.

    Article  CAS  PubMed  Google Scholar 

  49. Weterman MA, van Ruissen F, de Wissel M, Bordewijk L, Samijn JP, van der Pol WL et al. Copy number variation upstream of PMP22 in Charcot-Marie-Tooth disease. Eur J Hum Genet 2010; 18: 421–428.

    Article  CAS  PubMed  Google Scholar 

  50. Hammock EA, Levitt P . Developmental expression mapping of a gene implicated in multiple neurodevelopmental disorders, a2bp1 (fox1). Dev Neurosci 2011; 33: 64–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bhalla K, Phillips HA, Crawford J, McKenzie OL, Mulley JC, Eyre H et al. The de novo chromosome 16 translocations of two patients with abnormal phenotypes (mental retardation and epilepsy) disrupt the A2BP1 gene. J Hum Genet 2004; 49: 308–311.

    Article  PubMed  Google Scholar 

  52. Martin CL, Duvall JA, Ilkin Y, Simon JS, Arreaza MG, Wilkes K et al. Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism. Am J Med Genet B Neuropsychiatr Genet 2007; 144B: 869–876.

    Article  CAS  PubMed  Google Scholar 

  53. Barnby G, Abbott A, Sykes N, Morris A, Weeks DE, Mott R et al. Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT. Am J Hum Genet 2005; 76: 950–966.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wegerer M, Adena S, Pfennig A, Czamara D, Sailer U, Bettecken T et al. Variants within the GABA transaminase (ABAT) gene region are associated with somatosensory evoked EEG potentials in families at high risk for affective disorders. Psychol Med 2013; 43: 1207–1217.

    Article  CAS  PubMed  Google Scholar 

  55. Aiga M, Levinson JN, Bamji SX . N-cadherin and neuroligins cooperate to regulate synapse formation in hippocampal cultures. J Biol Chem 2011; 286: 851–858.

    Article  CAS  PubMed  Google Scholar 

  56. Lefort CT, Wojciechowski K, Hocking DC . N-cadherin cell-cell adhesion complexes are regulated by fibronectin matrix assembly. J Biol Chem 2011; 286: 3149–3160.

    Article  CAS  PubMed  Google Scholar 

  57. Malinverno M, Carta M, Epis R, Marcello E, Verpelli C, Cattabeni F et al. Synaptic localization and activity of ADAM10 regulate excitatory synapses through N-cadherin cleavage. J Neurosci 2010; 30: 16343–16355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rieger S, Senghaas N, Walch A, Koster RW . Cadherin-2 controls directional chain migration of cerebellar granule neurons. PLoS Biol 2009; 7: e1000240.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Tan ZJ, Peng Y, Song HL, Zheng JJ, Yu X . N-cadherin-dependent neuron-neuron interaction is required for the maintenance of activity-induced dendrite growth. Proc Natl Acad Sci USA 2010; 107: 9873–9878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Andreyeva A, Nieweg K, Horstmann K, Klapper S, Muller-Schiffmann A, Korth C et al. C-terminal fragment of N-cadherin accelerates synapse destabilization by amyloid-beta. Brain 2012; 135 (Pt 7): 2140–2154.

    Article  PubMed  Google Scholar 

  61. Ando K, Uemura K, Kuzuya A, Maesako M, Asada-Utsugi M, Kubota M et al. N-cadherin regulates p38 MAPK signaling via association with JNK-associated leucine zipper protein: implications for neurodegeneration in Alzheimer disease. J Biol Chem 2011; 286: 7619–7628.

    Article  CAS  PubMed  Google Scholar 

  62. Orioli D, Klein R . The Eph receptor family: axonal guidance by contact repulsion. Trends Genet 1997; 13: 354–359.

    Article  CAS  PubMed  Google Scholar 

  63. Savelieva KV, Rajan I, Baker KB, Vogel P, Jarman W, Allen M et al. Learning and memory impairment in Eph receptor A6 knockout mice. Neurosci Lett 2008; 438: 205–209.

    Article  CAS  PubMed  Google Scholar 

  64. Hayashi S, Imoto I, Aizu Y, Okamoto N, Mizuno S, Kurosawa K et al. Clinical application of array-based comparative genomic hybridization by two-stage screening for 536 patients with mental retardation and multiple congenital anomalies. J Hum Genet 2011; 56: 110–124.

    Article  CAS  PubMed  Google Scholar 

  65. Willour VL, Yao Shugart Y, Samuels J, Grados M, Cullen B, Bienvenu OJ 3rd et al. Replication study supports evidence for linkage to 9p24 in obsessive-compulsive disorder. Am J Hum Genet 2004; 75: 508–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Funk KE, Mrak RE, Kuret J . Granulovacuolar degeneration (GVD) bodies of Alzheimer's disease (AD) resemble late-stage autophagic organelles. Neuropathol Appl Neurobiol 2011; 37: 295–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yamazaki Y, Takahashi T, Hiji M, Kurashige T, Izumi Y, Yamawaki T et al. Immunopositivity for ESCRT-III subunit CHMP2B in granulovacuolar degeneration of neurons in the Alzheimer's disease hippocampus. Neurosci Lett 2010; 477: 86–90.

    Article  CAS  PubMed  Google Scholar 

  68. Sun Y, Zhang F, Gao J, Gao X, Guo T, Zhang K et al. Positive association between POU1F1 and mental retardation in young females in the Chinese Han population. Hum Mol Genet 2006; 15: 1237–1243.

    Article  CAS  PubMed  Google Scholar 

  69. Turton JP, Reynaud R, Mehta A, Torpiano J, Saveanu A, Woods KS et al. Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency. J Clin Endocrinol Metab 2005; 90: 4762–4770.

    Article  CAS  PubMed  Google Scholar 

  70. Urwin H, Authier A, Nielsen JE, Metcalf D, Powell C, Froud K et al. Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations. Hum Mol Genet 2010; 19: 2228–2238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE . Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 2007; 39: 17–23.

    Article  CAS  PubMed  Google Scholar 

  72. Carter CJ . Convergence of genes implicated in Alzheimer's disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis. Neurochem Int 2007; 50: 12–38.

    Article  CAS  PubMed  Google Scholar 

  73. Forster E, Bock HH, Herz J, Chai X, Frotscher M, Zhao S . Emerging topics in Reelin function. Eur J Neurosci 2010; 31: 1511–1518.

    PubMed  PubMed Central  Google Scholar 

  74. Rovelet-Lecrux A, Campion D . Copy number variations involving the microtubule-associated protein tau in human diseases. Biochem Soc Trans 2012; 40: 672–676.

    Article  CAS  PubMed  Google Scholar 

  75. Rovelet-Lecrux A, Hannequin D, Guillin O, Legallic S, Jurici S, Wallon D et al. Frontotemporal dementia phenotype associated with MAPT gene duplication. J Alzheimers Dis 2010; 21: 897–902.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was funded by grants from the NIMH and the Cure Alzheimer’s Fund.

Author information

Authors and Affiliations

  1. Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA

    B V Hooli, K Mullin, M A Blumenthal, C Zhang & R E Tanzi

  2. Department of Information Engineering, University of Brescia, Brescia, Italy

    Z M Kovacs-Vajna

  3. Channing Laboratory, Brigham and Women’s Hospital, Boston, MA, USA

    M Mattheisen

  4. Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA

    C Lange

  5. Molecular Pathology Unit, Massachusetts General Hospital, Boston, MA, USA

    G Mohapatra

  6. Max-Planck Institute for Molecular Genetics, Neuropsychiatric Genetics Group, Berlin, Germany

    L Bertram

Authors
  1. B V Hooli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Z M Kovacs-Vajna
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Mullin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M A Blumenthal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Mattheisen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Lange
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G Mohapatra
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Bertram
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R E Tanzi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R E Tanzi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hooli, B., Kovacs-Vajna, Z., Mullin, K. et al. Rare autosomal copy number variations in early-onset familial Alzheimer’s disease. Mol Psychiatry 19, 676–681 (2014). https://doi.org/10.1038/mp.2013.77

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2013.77

Keywords

This article is cited by

Search

Advanced search

Quick links