title: C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice.
abstract: The expansion of a hexanucleotide (GGGGCC) repeat in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both the function of C9ORF72 and the mechanism by which the repeat expansion drives neuropathology are unknown. To examine whether C9ORF72 haploinsufficiency induces neurological disease, we created a C9orf72-deficient mouse line. Null mice developed a robust immune phenotype characterized by myeloid expansion, T cell activation, and increased plasma cells. Mice also presented with elevated autoantibodies and evidence of immune-mediated glomerulonephropathy. Collectively, our data suggest that C9orf72 regulates immune homeostasis and an autoimmune response reminiscent of systemic lupus erythematosus (SLE) occurs in its absence. We further imply that haploinsufficiency is unlikely to be the causative factor in C9ALS/FTD pathology.
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Atanasio
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Vilma
authors.initials: V
authors.lastname: Decman
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Derek
authors.initials: D
authors.lastname: White
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Meg
authors.initials: M
authors.lastname: Ramos
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Burcin
authors.initials: B
authors.lastname: Ikiz
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Hoi-Ching
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Chia-Jen
authors.initials: CJ
authors.lastname: Siao
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Susannah
authors.initials: S
authors.lastname: Brydges
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: LaRosa
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Fury
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Burfeind
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Ralica
authors.initials: R
authors.lastname: Zamfirova
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Gregg
authors.initials: G
authors.lastname: Warshaw
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Orengo
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Adelekan
authors.initials: A
authors.lastname: Oyejide
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Fralish
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Wojtek
authors.initials: W
authors.lastname: Auerbach
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: William
authors.initials: W
authors.lastname: Poueymirou
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Freudenberg
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Guochun
authors.initials: G
authors.lastname: Gong
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Zambrowicz
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: David
authors.initials: D
authors.lastname: Valenzuela
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: George
authors.initials: G
authors.lastname: Yancopoulos
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Murphy
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.affiliation: Regeneron Pharmaceuticals, Inc, Tarrytown, NY USA.
authors.forename: Ka-Man Venus
authors.initials: KM
authors.lastname: Lai
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis* / Q000097:blood; D015551:Autoimmunity; D000073885:C9orf72 Protein; D016207:Cytokines / Q000097:blood; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative / Q000097:blood / Q000235:genetics* / Q000276:immunology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D008221:Lymphoid Tissue / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010950:Plasma Cells / Q000276:immunology; D017423:Sequence Analysis, RNA; D059467:Transcriptome
chemical_list: D001323:Autoantibodies; D000073885:C9orf72 Protein; C000606498:C9orf72 protein, mouse; D016207:Cytokines; D020662:Guanine Nucleotide Exchange Factors