Homozygous grn mutations: new phenotypes ...
Document type :
Article dans une revue scientifique: Article original
DOI :
PMID :
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Title :
Homozygous grn mutations: new phenotypes and new insights into pathological and molecular mechanisms
Author(s) :
Huin, Vincent [Auteur]
Barbier, Mathieu [Auteur]
Bottani, Armand [Auteur]
Lobrinus, Johannes Alexander [Auteur]
Clot, Fabienne [Auteur]
Lamari, Foudil [Auteur]
Chat, Laureen [Auteur]
Rucheton, Benoit [Auteur]
Fluchere, Frederique [Auteur]
Auvin, Stephane [Auteur]
Myers, Peter [Auteur]
Gelot, Antoinette [Auteur]
Camuzat, Agnes [Auteur]
Caillaud, Catherine [Auteur]
Jornea, Ludmila [Auteur]
Forlani, Sylvie [Auteur]
Saracino, Dario [Auteur]
Duyckaerts, Charles [Auteur]
Brice, Alexis [Auteur]
Durr, Alexandra [Auteur]
Le Ber, Isabelle [Auteur]
![refId](/themes/Mirage2//images/idref.png)
Barbier, Mathieu [Auteur]
Bottani, Armand [Auteur]
Lobrinus, Johannes Alexander [Auteur]
Clot, Fabienne [Auteur]
Lamari, Foudil [Auteur]
Chat, Laureen [Auteur]
Rucheton, Benoit [Auteur]
Fluchere, Frederique [Auteur]
Auvin, Stephane [Auteur]
Myers, Peter [Auteur]
Gelot, Antoinette [Auteur]
Camuzat, Agnes [Auteur]
Caillaud, Catherine [Auteur]
Jornea, Ludmila [Auteur]
Forlani, Sylvie [Auteur]
Saracino, Dario [Auteur]
Duyckaerts, Charles [Auteur]
Brice, Alexis [Auteur]
Durr, Alexandra [Auteur]
Le Ber, Isabelle [Auteur]
Journal title :
Brain . a journal of neurology
Abbreviated title :
Brain
Volume number :
143
Pages :
303-319
Publication date :
2020-01-01
ISSN :
1460-2156
Keyword(s) :
progranulin/GRN
frontotemporal dementia/frontotemporal lobar degeneration
TDP-43
cerebellar ataxia
neuronal ceroid lipofuscinosis
frontotemporal dementia/frontotemporal lobar degeneration
TDP-43
cerebellar ataxia
neuronal ceroid lipofuscinosis
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
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 ...
Show more >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.Show less >
Show more >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.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
CHU Lille
Inserm
Université de Lille
Inserm
Université de Lille
Collections :
Research team(s) :
Alzheimer et Tauopathies
Submission date :
2021-06-23T13:45:30Z