Homozygous GRN mutations: unexpected phenotypes and new insights into pathological and molecular mechanisms
Creators: name: Huin, Vincent
name: Barbier, Mathieu
name: Bottani, Armand
name: Lobrinus, Johannes
name: Clot, Fabienne
name: Lamari, Foudil
name: Chat, Laureen
name: Rucheton, Benoît
name: Fluchère, Frédérique
name: Auvin, Stéphane
name: Myers, Peter
name: Gelot, Antoinette
name: Camuzat, Agnès
name: Caillaud, Catherine
name: Jornéa, Ludmila
name: Forlani, Sylvie
name: Saracino, Dario
name: Duyckaerts, Charles
name: Brice, Alexis
name: Durr, Alexandra
name: Ber, Isabelle Le
Publisher: name: arXiv
Year: 2020
Subjects: subject: Biomolecules (q-bio.BM)
subject: Genomics (q-bio.GN)
subject: Neurons and Cognition (q-bio.NC)
subject: FOS: Biological sciences
subject: FOS: Biological sciences

description: 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.