Homozygous GRN mutations: unexpected phenotypes and new insights into pathological and molecular mechanisms
| Autor: | HUIN, Vincent, Barbier, Mathieu, Bottani, Armand, Lobrinus, Johannes, Clot, Fabienne, Lamari, Foudil, Chat, Laureen, Rucheton, Benoît, Fluchère, Frédérique, Auvin, Stéphane, Myers, Peter, Gelot, Antoinette, Camuzat, Agnès, Caillaud, Catherine, Jornéa, Ludmila, Forlani, Sylvie, Saracino, Dario, Duyckaerts, Charles, Brice, Alexis, Durr, Alexandra, Le Ber, Isabelle |
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| Přispěvatelé: | Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Geneva University Hospital (HUG), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université de Paris (UP), Medical Office [Geneva, Switzerland], Service de pathologie [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neuropathologie [CHU Pitié Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Sorbonne Université, Institut du Cerveau et de la Moelle épinière (ICM), AP-HP, INSERM, CNRS, University Hospital Pitié - Salpêtrière, Paris, France |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
MESH: Rare Diseases
Progranulin MESH: Mutation MESH: Epilepsy / genetics MESH: Frontotemporal Dementia / genetics TDP-43 MESH: Age of Onset MESH: Neuronal Ceroid-Lipofuscinoses / diagnostic imaging MESH: Parkinsonian Disorders / physiopathology MESH: TDP-43 Proteinopathies / physiopathology MESH: RNA Splicing / genetics MESH: Frontotemporal Dementia / diagnostic imaging MESH: Child MESH: Cerebellar Ataxia / genetics [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] MESH: Retinitis Pigmentosa / genetics [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] Cerebellar ataxia MESH: Heterozygote MESH: Adolescent MESH: Humans MESH: Middle Aged MESH: Progranulins / genetics MESH: Adult [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology MESH: TDP-43 Proteinopathies / diagnostic imaging MESH: Male [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biomolecules [q-bio.BM] Neuronal ceroid lipofuscinosis MESH: Neuronal Ceroid-Lipofuscinoses / physiopathology MESH: Parkinsonian Disorders / genetics frontotemporal lobar degeneration MESH: Cognitive Dysfunction / genetics [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics MESH: Young Adult MESH: Parkinsonian Disorders / diagnostic imaging MESH: TDP-43 Proteinopathies / genetics [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] MESH: Frontotemporal Dementia / physiopathology MESH: Neuronal Ceroid-Lipofuscinoses / genetics MESH: Female Frontotemporal dementia GRN [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology MESH: Homozygote MESH: Progranulins / metabolism |
| Zdroj: | Brain-A Journal of Neurology Brain-A Journal of Neurology, Oxford University Press (OUP), 2020, 143 (1), pp.303-319. ⟨10.1093/brain/awz377⟩ |
| ISSN: | 0006-8950 1460-2156 |
| DOI: | 10.1093/brain/awz377⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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