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Loss of DPP6 in neurodegenerative dementia : a genetic player in the dysfunction of neuronal excitability

(2019) ACTA NEUROPATHOLOGICA. 137(6). p.901-918
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Abstract
Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frame-shift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel K(v)4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or K(v)4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate.
Keywords
Neurodegenerative brain diseases, Dementia, DPP6, Hyperexcitability, Whole genome sequencing, Oxford nanopore technologies (ONT) PromethION, FRONTOTEMPORAL LOBAR DEGENERATION, ALZHEIMERS-DISEASE, PROTEIN DPPX, DENDRITIC EXCITABILITY, STRUCTURAL VARIATION, BEHAVIORAL VARIANT, NATIONAL INSTITUTE, MUTATION, ASSOCIATION, C9ORF72

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MLA
Cacace, Rita, et al. “Loss of DPP6 in Neurodegenerative Dementia : A Genetic Player in the Dysfunction of Neuronal Excitability.” ACTA NEUROPATHOLOGICA, vol. 137, no. 6, 2019, pp. 901–18, doi:10.1007/s00401-019-01976-3.
APA
Cacace, R., Heeman, B., Van Mossevelde, S., De Roeck, A., Hoogmartens, J., De Rijk, P., … De Klippel, N. (2019). Loss of DPP6 in neurodegenerative dementia : a genetic player in the dysfunction of neuronal excitability. ACTA NEUROPATHOLOGICA, 137(6), 901–918. https://doi.org/10.1007/s00401-019-01976-3
Chicago author-date
Cacace, Rita, Bavo Heeman, Sara Van Mossevelde, Arne De Roeck, Julie Hoogmartens, Peter De Rijk, Helena Gossye, et al. 2019. “Loss of DPP6 in Neurodegenerative Dementia : A Genetic Player in the Dysfunction of Neuronal Excitability.” ACTA NEUROPATHOLOGICA 137 (6): 901–18. https://doi.org/10.1007/s00401-019-01976-3.
Chicago author-date (all authors)
Cacace, Rita, Bavo Heeman, Sara Van Mossevelde, Arne De Roeck, Julie Hoogmartens, Peter De Rijk, Helena Gossye, Kristof De Vos, Wouter De Coster, Mojca Strazisar, Greet De Baets, Joost Schymkowitz, Frederic Rousseau, Nathalie Geerts, Tim De Pooter, Karin Peeters, Anne Sieben, Jean-Jacques Martin, Sebastiaan Engelborghs, Eric Salmon, Patrick Santens, Rik Vandenberghe, Patrick Cras, Peter P De Deyn, John C van Swieten, Cornelia M van Duijn, Julie van der Zee, Kristel Sleegers, Christine Van Broeckhoven, on behalf of the BELNEU Consortium, Johan Goeman, Roeland Crols, Dirk Nuytten, Jan De Bleecker, Tim Van Langenhove, Adrian Ivanoiu, Olivier Deryck, Bruno Bergmans, Jan Versijpt, Alex Michotte, Jean Delbeck, Christiana Willems, and Nina De Klippel. 2019. “Loss of DPP6 in Neurodegenerative Dementia : A Genetic Player in the Dysfunction of Neuronal Excitability.” ACTA NEUROPATHOLOGICA 137 (6): 901–918. doi:10.1007/s00401-019-01976-3.
Vancouver
1.
Cacace R, Heeman B, Van Mossevelde S, De Roeck A, Hoogmartens J, De Rijk P, et al. Loss of DPP6 in neurodegenerative dementia : a genetic player in the dysfunction of neuronal excitability. ACTA NEUROPATHOLOGICA. 2019;137(6):901–18.
IEEE
[1]
R. Cacace et al., “Loss of DPP6 in neurodegenerative dementia : a genetic player in the dysfunction of neuronal excitability,” ACTA NEUROPATHOLOGICA, vol. 137, no. 6, pp. 901–918, 2019.
@article{8618354,
  abstract     = {{Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frame-shift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel K(v)4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or K(v)4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate.}},
  author       = {{Cacace, Rita and Heeman, Bavo and Van Mossevelde, Sara and De Roeck, Arne and Hoogmartens, Julie and De Rijk, Peter and Gossye, Helena and De Vos, Kristof and De Coster, Wouter and Strazisar, Mojca and De Baets, Greet and Schymkowitz, Joost and Rousseau, Frederic and Geerts, Nathalie and De Pooter, Tim and Peeters, Karin and Sieben, Anne and Martin, Jean-Jacques and Engelborghs, Sebastiaan and Salmon, Eric and Santens, Patrick and Vandenberghe, Rik and Cras, Patrick and De Deyn, Peter P and van Swieten, John C and van Duijn, Cornelia M and van der Zee, Julie and Sleegers, Kristel and Van Broeckhoven, Christine and BELNEU Consortium, on behalf of the and Goeman, Johan and Crols, Roeland and Nuytten, Dirk and De Bleecker, Jan and Van Langenhove, Tim and Ivanoiu, Adrian and Deryck, Olivier and Bergmans, Bruno and Versijpt, Jan and Michotte, Alex and Delbeck, Jean and Willems, Christiana and De Klippel, Nina}},
  issn         = {{0001-6322}},
  journal      = {{ACTA NEUROPATHOLOGICA}},
  keywords     = {{Neurodegenerative brain diseases,Dementia,DPP6,Hyperexcitability,Whole genome sequencing,Oxford nanopore technologies (ONT) PromethION,FRONTOTEMPORAL LOBAR DEGENERATION,ALZHEIMERS-DISEASE,PROTEIN DPPX,DENDRITIC EXCITABILITY,STRUCTURAL VARIATION,BEHAVIORAL VARIANT,NATIONAL INSTITUTE,MUTATION,ASSOCIATION,C9ORF72}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{901--918}},
  title        = {{Loss of DPP6 in neurodegenerative dementia : a genetic player in the dysfunction of neuronal excitability}},
  url          = {{http://doi.org/10.1007/s00401-019-01976-3}},
  volume       = {{137}},
  year         = {{2019}},
}

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