Homozygous GRN mutations: unexpected phenotypes and new insights into pathological and molecular mechanisms - Archive ouverte HAL Access content directly
Journal Articles Brain - A Journal of Neurology Year : 2020

Homozygous GRN mutations: unexpected phenotypes and new insights into pathological and molecular mechanisms

Mutations homozygotes du gène GRN : phénotypes inattendus et nouvelles connaissances sur les mécanismes pathologiques et moléculaires

(1) , (1) , (2) , (2) , (3) , (3) , (3) , (3) , (4, 5) , (6) , (7) , (8, 9) , (1) , (10) , (1) , (1) , (1) , (11) , (1, 3) , (3, 1) , (1, 12)
1
2
3
4
5
6
7
8
9
10
11
12
Vincent Huin
Dario Saracino

Abstract

Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counseling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis.
Fichier principal
Vignette du fichier
Huin.Brain.2020.Author.version.pdf (1.46 Mo) Télécharger le fichier
Origin : Files produced by the author(s)

Dates and versions

inserm-03014481 , version 1 (19-11-2020)
inserm-03014481 , version 2 (20-11-2020)

Identifiers

Cite

Vincent Huin, Mathieu Barbier, Armand Bottani, Johannes Alexander Lobrinus, Fabienne Clot, et al.. Homozygous GRN mutations: unexpected phenotypes and new insights into pathological and molecular mechanisms: New insights in homozygous GRN mutations. Brain - A Journal of Neurology , 2020, 143 (1), pp.303-319. ⟨10.1093/brain/awz377⟩. ⟨inserm-03014481v2⟩
293 View
235 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More