en
Scientific article
English

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

Published inBrain, vol. 143, no. 1, p. 303-319
Publication date2020
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 counselling 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.

Citation (ISO format)
HUIN, Vincent et al. Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms. In: Brain, 2020, vol. 143, n° 1, p. 303–319. doi: 10.1093/brain/awz377
Main files (1)
Article (Published version)
accessLevelRestricted
Secondary files (1)
Identifiers
ISSN of the journal0006-8950
318views
1downloads

Technical informations

Creation01/30/2020 5:22:00 PM
First validation01/30/2020 5:22:00 PM
Update time03/15/2023 9:06:45 PM
Status update03/15/2023 9:06:42 PM
Last indexation01/17/2024 8:56:30 AM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack