Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability.
Action Potentials
/ physiology
Adult
Aged
Chromosome Inversion
Chromosomes, Human, Pair 7
/ genetics
Dementia
/ genetics
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
/ deficiency
Female
Genes, Dominant
Homeostasis
Humans
Male
Middle Aged
Mutation
Nerve Tissue Proteins
/ deficiency
Neurodegenerative Diseases
/ genetics
Neurons
/ physiology
Pedigree
Penetrance
Polymorphism, Single Nucleotide
Potassium Channels
/ deficiency
Protein Stability
Protein Transport
Synaptic Transmission
Whole Genome Sequencing
DPP6
Dementia
Hyperexcitability
Neurodegenerative brain diseases
Oxford nanopore technologies (ONT) PromethION
Whole genome sequencing
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
03
12
2018
accepted:
13
02
2019
revised:
07
02
2019
pubmed:
16
3
2019
medline:
23
6
2020
entrez:
16
3
2019
Statut:
ppublish
Résumé
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. 4 Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frameshift, 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
Identifiants
pubmed: 30874922
doi: 10.1007/s00401-019-01976-3
pii: 10.1007/s00401-019-01976-3
pmc: PMC6531610
doi:
Substances chimiques
Nerve Tissue Proteins
0
Potassium Channels
0
DPP6 protein, human
EC 3.4.-
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
EC 3.4.14.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
901-918Investigateurs
Johan Goeman
(J)
Roeland Crols
(R)
Dirk Nuytten
(D)
Jan L De Bleecker
(JL)
Tim Van Langenhove
(T)
Adrian Ivanoiu
(A)
Olivier Deryck
(O)
Bruno Bergmans
(B)
Jan Versijpt
(J)
Alex Michotte
(A)
Jean Delbeck
(J)
Christiana Willems
(C)
Nina De Klippel
(N)
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