De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease



We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aβ) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient’s RNA, leading to a pathogenic missense at exons 8–10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aβ secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aβ-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aβ network alteration in AD.

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Sponsored by CNR-MAJ and supported by grants from the Clinical Research Hospital Program from the French Ministry of Health (GMAJ, PHRC 2008/067). MNJS and SYB are funded through grants (G0701444 and MR/L007533/1) from the Medical Research Council awarded to MNJS. PJ is supported by grant BT/PR15118/BID/07/357/2011 from the Department of Biotechnology, Government of India. We thank the Integragen company for exome sequencing. We thank Pascal Chambon, Géraldine Joly, Soumeya Bekri and Stéphanie Torre for cultured fibroblasts, and Alessandro Beghini for the MARK4 plasmid. We thank Magalie Lecourtois and Emmanuelle Genin for helpful discussions and Tracey Avequin for editing the manuscript.

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Correspondence to D Campion.

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The authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

Appendix A

Appendix A CNR-MAJ Collaborators

Claire Boutoleau-Bretonnière1, Mathieu Ceccaldi2, Julien Cogez3, Bernard Croisile4, Olivier Felician2, Annie Laquerrière5, Isabelle Le Ber6,7, Andre Maues De Paula8, Olivier Moreaud9, Jérémie Pariente10, Florence Pasquier11,12, Adeline Rollin-Sillaire11,12, Olivier Rouaud13, François Sellal14, Christel Thauvin15

Collaborators affiliations

1Department of Neurology, CMRR, Nantes University Hospital, Nantes, France.

2Neurology and Neuropsychology department, AP-HM La Timône Marseille University Hospital & INSERM UMR1106, University of Aix-Marseille, Marseille, France.

3Department of Neurology, CMRR, Caen University Hospital, Caen, France.

4Department of Neuropsychology, CMRR, Groupe Hospitalier Est, University Hospital, Bron, France.

5Neuropathology Laboratory, Rouen University Hospital, Rouen, France.

6CNR-MAJ, University Hospital of Paris La Pitié-Salpêtrière, Paris, France.

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

8Neuropathology Laboratory, AP-HM La Timône Marseille University Hospital, Marseille, France.

9Department of Neurology, CMRR, Grenoble University Hospital, Grenoble, France.

10Neurology Department, CMRR, Purpan University Hospital, Toulouse, France.

11CNR-MAJ, University Hospital of Lille, Lille, France.

12CMRR, Lille University Hospital & EA1040 Université Lille Nord de France, Lille, France.

13Memory Centre, Department of Neurology, Centre Georges François Leclerc, University Hospital, Dijon, France.

14Department of Neurology, CMRR, Hôpitaux Civils de Colmar, Colmar, France.

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

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