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

• Published in: Brain (London, England : 1878) England : 1878), 2020-01, Vol.143 (1), p.303-319
• Main Authors: Huin, Vincent, Barbier, Mathieu, Bottani, Armand, Lobrinus, Johannes Alexander, 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
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Age of Onset; Cerebellar Ataxia - genetics; Child; Cognitive Dysfunction - genetics; Epilepsy - genetics; Female; Frontotemporal Dementia - diagnostic imaging; Frontotemporal Dementia - genetics; Frontotemporal Dementia - physiopathology; Heterozygote; Homozygote; Humans; Male; Middle Aged; Mutation; Neuronal Ceroid-Lipofuscinoses - diagnostic imaging; Neuronal Ceroid-Lipofuscinoses - genetics; Neuronal Ceroid-Lipofuscinoses - physiopathology; Parkinsonian Disorders - diagnostic imaging; Parkinsonian Disorders - genetics; Parkinsonian Disorders - physiopathology; Progranulins - genetics; Progranulins - metabolism; Rare Diseases; Retinitis Pigmentosa - genetics; RNA Splicing - genetics; TDP-43 Proteinopathies - diagnostic imaging; TDP-43 Proteinopathies - genetics; TDP-43 Proteinopathies - physiopathology; Young Adult
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awz377

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