Back to Search
Start Over
Missense mutation in GRN gene affecting RNA splicing and plasma progranulin level in a family affected by frontotemporal lobar degeneration
- Source :
- Neurobiology of Aging. 54:214.e1-214.e6
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- Gene coding for progranulin, GRN, is a major gene linked to frontotemporal lobar degeneration. While most of pathogenic GRN mutations are null mutations leading to haploinsufficiency, GRN missense mutations do not have an obvious pathogenicity, and only a few have been revealed to act through different pathogenetic mechanisms, such as cytoplasmic missorting, protein degradation, and abnormal cleavage by elastase. The aim of this study was to disclose the pathogenetic mechanisms of the GRN A199V missense mutation, which was previously reported not to alter physiological progranulin features but was associated with a reduced plasma progranulin level. After investigating the family pedigree, we performed genetic and biochemical analysis on its members and performed RNA expression studies. We found that the mutation segregates with the disease and discovered that its pathogenic feature is the alteration of GRN mRNA splicing, actually leading to haploinsufficiency. Thus, when facing with a missense GRN mutation, its pathogenetic effects should be investigated, especially if associated with low plasma progranulin levels, to determine its nature of either benign polymorphism or pathogenic mutation.
- Subjects :
- Male
0301 basic medicine
Aging
RNA Splicing
Mutation, Missense
Disease
Biology
Protein degradation
03 medical and health sciences
Progranulins
0302 clinical medicine
mental disorders
medicine
Humans
Missense mutation
Gene
Genetic Association Studies
Aged
Genetics
General Neuroscience
Frontotemporal lobar degeneration
Middle Aged
medicine.disease
Major gene
Pedigree
030104 developmental biology
RNA splicing
Intercellular Signaling Peptides and Proteins
Female
Neurology (clinical)
Frontotemporal Lobar Degeneration
Geriatrics and Gerontology
Haploinsufficiency
030217 neurology & neurosurgery
Developmental Biology
Subjects
Details
- ISSN :
- 01974580
- Volume :
- 54
- Database :
- OpenAIRE
- Journal :
- Neurobiology of Aging
- Accession number :
- edsair.doi.dedup.....ade15446518bd418a45be03deaa69bbf