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High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease

Molecular Psychiatry volume 17, pages 875–879 (2012)Cite this article

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Abstract

Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n=1) or missense (n=4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.

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References

  1. Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M et al. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet 1999; 65: 664–670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerrière 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 

  3. Rovelet-Lecrux A, Legallic S, Wallon D, Flaman JM, Martinaud O, Bombois S et al. A genome wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease. Eur J Hum Genet; advance online publication 14 December 2011 (e-pub ahead of print).

  4. Alperovitch A, Amouyel P, Dartigues JF, Ducimetière P, Mazoyer B, Ritchie K et al. [Epidemiological studies on aging in France: from the PAQUID study to the Three-City study]. C R Biol 2002; 325: 665–672.

    Article  PubMed  Google Scholar 

  5. Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 2007; 39: 168–177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Reitz C, Cheng R, Rogaeva E, Lee JH, Tokuhiro S, Zou F et al. Meta-analysis of the association between variants in SORL1 and Alzheimer disease. Arch Neurol 2011; 68: 99–106.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Schwarz JM, Rodelsperger C, Schuelke M, Seelow D . MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 2010; 7: 575–576.

    Article  CAS  PubMed  Google Scholar 

  8. Andersen OM, Schmidt V, Spoelgen R, Gliemann J, Behlke J, Galatis D et al. Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11. Biochemistry 2006; 45: 2618–2628.

    Article  CAS  PubMed  Google Scholar 

  9. Hermey G . The Vps10p-domain receptor family. Cell Mol Life Sci 2009; 66: 2677–2689.

    Article  CAS  PubMed  Google Scholar 

  10. Ng SB, Nickerson DA, Bamshad MJ, Shendure J . Massively parallel sequencing and rare disease. Hum Mol Genet 2010; 19: R119–R124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the Clinical Research Hospital Program from the French Ministry of Health (GMAJ, PHRC 2008/067), to DH and DC, and sponsored by the University Hospital of Rouen. We thank the Integragen society, which performed exome sequencing. We thank the LITIS and the TIBS team for providing bioinformatics support, André Blavier for the Alamut software, Mario Tosi for helpful discussions, and Tracey Avequin for editing the manuscript.

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Author notes

  1. C Pottier, D Hannequin, S Coutant, A Rovelet-Lecrux, D Wallon, S Rousseau, S Legallic, C Paquet, S Bombois, J Pariente, C Thomas-Anterion, A Michon, B Croisile, F Etcharry-Bouyx, C Berr, J-F Dartigues, P Amouyel, H Dauchel, C Boutoleau-Bretonnière, C Thauvin, T Frebourg, J-C Lambert and D Campion: PHRC GMAJ collaborators are listed in Appendix A.

Authors and Affiliations

  1. Department of Molecular Genetics, Inserm U614, Institute for Biomedical Research and Innovation, University of Rouen, Rouen, France

    C Pottier, D Hannequin, S Coutant, A Rovelet-Lecrux, D Wallon, S Rousseau, S Legallic, T Frebourg & D Campion

  2. CNR-MAJ, Rouen University Hospital, Lille University Hospital and Paris Salpêtrière University Hospital, France

    C Pottier, D Hannequin, S Coutant, A Rovelet-Lecrux, D Wallon, S Rousseau, S Legallic, S Bombois, A Michon & D Campion

  3. CMRR Nord, Inserm U839, Lariboisière University Hospital, Paris, France

    C Paquet

  4. EA1046, Lille Nord University Hospital, Lille, France

    S Bombois

  5. Department of Neurology, CMRR and Inserm U825, Purpan University Hospital, Toulouse, France

    J Pariente

  6. Department of Neurology, CMRR, University Hospital Nord, Saint Etienne, France

    C Thomas-Anterion

  7. CRCICM, IM2A, UMR-S975 AP-HP, University Hospital Pitié-Salpêtrière, Paris, France

    A Michon

  8. Department of Neuropsychology, CMRR, University Hospital, Groupe Hospitalier Est, Bron, France

    B Croisile

  9. Department of Neurology, Angers University Hospital, Angers, France

    F Etcharry-Bouyx

  10. INSERM U888, Hôpital La Colombière, Montpellier, France

    C Berr

  11. INSERM U897, Victor Segalen University, Bordeaux, France

    J-F Dartigues

  12. INSERM U744, Pasteur Institute of Lille, Lille, France

    P Amouyel & J-C Lambert

  13. LITIS, EA 4108, University of Rouen, Rouen, France

    H Dauchel

  14. Department of Neurology, CMRR, Nantes University Hospital, Nantes, France

    C Boutoleau-Bretonnière

  15. Department of Genetics, Dijon University Hospital, Dijon, France

    C Thauvin

  16. Le Rouvray Hospital, Sotteville les Rouen, France

    D Campion

Authors
  1. C Pottier
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  2. D Hannequin
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  7. S Legallic
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  8. C Paquet
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  9. S Bombois
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  10. J Pariente
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  13. B Croisile
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  14. F Etcharry-Bouyx
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  17. P Amouyel
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  18. H Dauchel
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  19. C Boutoleau-Bretonnière
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  20. C Thauvin
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  21. T Frebourg
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  22. J-C Lambert
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  23. D Campion
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Consortia

PHRC GMAJ Collaborators

Corresponding author

Correspondence to D Campion.

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The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

Appendix A

Appendix A

PHRC GMAJ collaborators

The investigators of the French GMAJ project include Didier Hannequin, Dominique Campion, Olivier Martinaud, Lucie Guyant-Maréchal and David Wallon (Centre Hospitalo Universitaire (CHU), Rouen); Olivier Godefroy and Candice Picard (CHU Amiens); Frédérique Etcharry-Bouyx (CHU Angers); Eric Berger (CHU Besancon); Jean-Francois Dartigues and Sophie Auriacombe (CHU Bordeaux); Vincent de la Sayette (CHU Caen); Francois Sellal (CH Colmar); Olivier Rouaud and Christel Thauvin (CHU Dijon); Olivier Moreaud (CHU Grenoble); Stéphanie Bombois, Adeline Rollin-Sillaire, Marie-Anne Mackowiak and Florence Pasquier (CHU Lille); Isabelle Roullet-Solignac and Alain Vighetto (CHU Lyon); Mira Didic, Olivier Félician and Mathieu Ceccaldi (CHU Marseille); Audrey Gabelle and Jacques Touchon (CHU Montpellier); Martine Vercelletto and Claire Boutoleau-Bretonnière (CHU Nantes); Pierre Labauge and Giovanni Castelnovo (CHU Nimes); Claire Paquet and Jacques Hugon (CHU Lariboisière); Agnès Michon, Isabelle Le Ber and Bruno Dubois (CHU La Salpêtrière, Paris); Catherine Thomas-Antérion (CHU Saint-Etienne); Frédéric Blanc and Christine Tranchant (CHU Strasbourg); Jérémie Pariente, Michèle Puel and Jean-Francois Demonet (CHU Toulouse); Caroline Hommet and Karl Mondon (CHU Tours); Hélène Mollion and Bernard Croisile (CMRR CHU Lyon); Mathilde Sauvée (CHU Nancy); Gaelle Godenèche and Foucauld De Boisgueheneuc (CHU Poitiers).

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Pottier, C., Hannequin, D., Coutant, S. et al. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiatry 17, 875–879 (2012). https://doi.org/10.1038/mp.2012.15

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