{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:51:00Z","timestamp":1790725860062,"version":"4.1.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2019,12,19]],"date-time":"2019-12-19T00:00:00Z","timestamp":1576713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"VERUM","award":["ANR-11-INBS-0011 \u2013 NeurATRIS"],"award-info":[{"award-number":["ANR-11-INBS-0011 \u2013 NeurATRIS"]}]},{"name":"Translational Research Infrastructure for Biotherapies in Neurosciences"},{"name":"Programme Hospitalier de Recherche Clinique"},{"name":"PHRC"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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.<\/jats:p>","DOI":"10.1093\/brain\/awz377","type":"journal-article","created":{"date-parts":[[2019,11,13]],"date-time":"2019-11-13T20:10:44Z","timestamp":1573675844000},"page":"303-319","source":"Crossref","is-referenced-by-count":90,"title":["Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms"],"prefix":"10.1093","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8201-5406","authenticated-orcid":false,"given":"Vincent","family":"Huin","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, Institut du Cerveau et de la Moelle \u00e9pini\u00e8re (ICM), AP-HP, INSERM, CNRS, University Hospital Piti\u00e9-Salp\u00eatri\u00e8re, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5154-2163","authenticated-orcid":false,"given":"Mathieu","family":"Barbier","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Institut du Cerveau et de la Moelle \u00e9pini\u00e8re (ICM), AP-HP, INSERM, CNRS, University Hospital Piti\u00e9-Salp\u00eatri\u00e8re, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7146-1291","authenticated-orcid":false,"given":"Armand","family":"Bottani","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine, University Hospital of Geneva, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes Alexander","family":"Lobrinus","sequence":"additional","affiliation":[{"name":"Neuropathology Unit, University Hospital of Geneva, Geneva, 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