Genetic variants in progranulin upstream open reading frames increase downstream protein expression.
5' Untranslated Regions
/ genetics
Adult
Aged
Aged, 80 and over
Codon, Nonsense
/ genetics
Cohort Studies
Culture
Female
Frontotemporal Dementia
/ genetics
Frontotemporal Lobar Degeneration
/ genetics
Gene Expression
/ genetics
Humans
Loss of Function Mutation
/ genetics
Male
Middle Aged
Open Reading Frames
/ genetics
Progranulins
/ genetics
RNA, Messenger
/ genetics
FTD
Frontotemporal lobar degeneration
GRN gene
PGRN protein
Rare genetic variants
Upstream open reading frame
Journal
Neurobiology of aging
ISSN: 1558-1497
Titre abrégé: Neurobiol Aging
Pays: United States
ID NLM: 8100437
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
03
05
2021
revised:
29
08
2021
accepted:
05
09
2021
pubmed:
9
10
2021
medline:
15
2
2022
entrez:
8
10
2021
Statut:
ppublish
Résumé
Premature termination codon (PTC) mutations in the granulin gene (GRN) lead to loss-of-function (LOF) of the progranulin protein (PGRN), causing frontotemporal lobar degeneration (FTLD) by haploinsufficiency. GRN expression is regulated at multiple levels, including the 5' untranslated region (UTR). The main 5' UTR of GRN and an alternative 5' UTR, contain upstream open reading frames (uORFs). These mRNA elements generally act as cis-repressors of translation. Disruption of each uORF of the alternative 5' UTR, increases protein expression with the 2 ATG-initiated uORFs being capable of initiating translation. We performed targeted sequencing of the uORF regions in a Flanders-Belgian cohort of patients with frontotemporal dementia (FTD) and identified 2 genetic variants, one in each 5' UTR. Both variants increase downstream protein levels, with the main 5' UTR variant rs76783532 causing a significant 1.5-fold increase in protein expression. We observed that the presence of functional uORFs in the alternative 5' UTR act as potential regulators of PGRN expression and demonstrate that genetic variation within GRN uORFs can alter their function.
Identifiants
pubmed: 34620513
pii: S0197-4580(21)00288-8
doi: 10.1016/j.neurobiolaging.2021.09.007
pii:
doi:
Substances chimiques
5' Untranslated Regions
0
Codon, Nonsense
0
Progranulins
0
RNA, Messenger
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
113-121Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors have no conflicts of interest.