title: Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis.
abstract: Heterozygous mutations in theGRNgene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. HomozygousGRNmutations, on the other hand, lead to complete PGRN loss and cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease usually seen in children. Given that the predominant clinical and pathological features of FTD and NCL are distinct, it is controversial whether the disease mechanisms associated with complete and partial PGRN loss are similar or distinct. We show that PGRN haploinsufficiency leads to NCL-like features in humans, some occurring before dementia onset. Noninvasive retinal imaging revealed preclinical retinal lipofuscinosis in heterozygousGRNmutation carriers. Increased lipofuscinosis and intracellular NCL-like storage material also occurred in postmortem cortex of heterozygousGRNmutation carriers. Lymphoblasts from heterozygousGRNmutation carriers accumulated prominent NCL-like storage material, which could be rescued by normalizing PGRN expression. Fibroblasts from heterozygousGRNmutation carriers showed impaired lysosomal protease activity. Our findings indicate that progranulin haploinsufficiency caused accumulation of NCL-like storage material and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process inGRN-associated FTD andGRN-associated NCL.
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.|National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.|Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Michael E
authors.identifier: 0000-0002-5296-8051
authors.initials: ME
authors.lastname: Ward
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.|Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94158, USA.|Department of Pathology, National Taiwan University Hospital, Taipei City, Taiwan.
authors.forename: Hsin-Yi
authors.identifier: 0000-0003-0062-3091
authors.initials: HY
authors.lastname: Huang
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.|Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Connor
authors.initials: C
authors.lastname: Ludwig
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
authors.forename: Maria
authors.identifier: 0000-0002-5237-4042
authors.initials: M
authors.lastname: Telpoukhovskaia
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
authors.forename: Ali
authors.identifier: 0000-0003-1746-3979
authors.initials: A
authors.lastname: Taubes
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94158, USA.|INSERM UMR 913, Université de Nantes, Nantes, France.
authors.forename: Helene
authors.initials: H
authors.lastname: Boudin
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
authors.forename: Sakura S
authors.initials: SS
authors.lastname: Minami
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
authors.forename: Meredith
authors.identifier: 0000-0002-5873-0490
authors.initials: M
authors.lastname: Reichert
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany.
authors.forename: Philipp
authors.identifier: 0000-0001-7987-658X
authors.initials: P
authors.lastname: Albrecht
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jeffrey M
authors.identifier: 0000-0002-5121-3319
authors.initials: JM
authors.lastname: Gelfand
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Andres
authors.identifier: 0000-0002-9629-1492
authors.initials: A
authors.lastname: Cruz-Herranz
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Christian
authors.identifier: 0000-0002-1413-0442
authors.initials: C
authors.lastname: Cordano
authors.affiliation: Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Marcel V
authors.identifier: 0000-0002-1319-3062
authors.initials: MV
authors.lastname: Alavi
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
authors.forename: Shannon
authors.identifier: 0000-0002-9009-6338
authors.initials: S
authors.lastname: Leslie
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Bruce L
authors.identifier: 0000-0002-2152-4220
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Bigio
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Marek-Marsel
authors.initials: MM
authors.lastname: Mesulam
authors.affiliation: Department of Pathology, Stanford Medical School, Palo Alto, CA 94305, USA.
authors.forename: Matthew S
authors.identifier: 0000-0003-3753-4412
authors.initials: MS
authors.lastname: Bogyo
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: Ian R
authors.identifier: 0000-0003-3875-2972
authors.initials: IR
authors.lastname: Mackenzie
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Staropoli
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Susan L
authors.identifier: 0000-0003-3114-0543
authors.initials: SL
authors.lastname: Cotman
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94158, USA.|Pathology Service, Veterans Affairs Medical Center, San Francisco, CA 94141, USA.
authors.forename: Eric J
authors.identifier: 0000-0002-5381-3801
authors.initials: EJ
authors.lastname: Huang
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA. lgan@gladstone.ucsf.edu agreen@ucsf.edu.|Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Li
authors.identifier: 0000-0003-2050-951X
authors.initials: L
authors.lastname: Gan
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. lgan@gladstone.ucsf.edu agreen@ucsf.edu.|Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Ari J
authors.identifier: 0000-0001-9275-3066
authors.initials: AJ
authors.lastname: Green
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005625:Frontal Lobe / Q000378:metabolism / Q000648:ultrastructure; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057895:Haploinsufficiency / Q000235:genetics / Q000502:physiology*; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D008247:Lysosomes; D051379:Mice; D008854:Microscopy, Electron; D009154:Mutation / Q000235:genetics; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000077153:Progranulins; D012160:Retina / Q000378:metabolism / Q000648:ultrastructure
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins