title: A Novel Loss-of-Function GRN Mutation p.(Tyr229*): Clinical and Neuropathological Features.
abstract: Mutations in the progranulin (GRN) gene represent about 5-10% of frontotemporal lobar degeneration (FTLD). We describe a proband with a novel GRN mutation c.687T>A, p.(Tyr229*), presenting with dyspraxia, dysgraphia, and dysphasia at the age of 60 and a very severe FTLD neuropathological phenotype with TDP43 inclusions. The nephew of the proband had signs of dementia and personality changes at the age of 60 and showed similar but milder FTLD pathology. Three other family members had had early-onset dementia. Gene expression studies showed decreased GRN gene expression in mutation carriers' blood samples. In conclusion, we describe a novel GRN, p.(Tyr229*) mutation, resulting in haploinsufficiency of GRN and a severe neuropathologic FTLD phenotype.
authors: Department of Clinical Genetics, Helsinki University Central Hospital and Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
authors: Liina
authors: L
authors: Kuuluvainen
authors: Department of Clinical Genetics, Helsinki University Central Hospital and Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
authors: Minna
authors: M
authors: Pöyhönen
authors: Department of Medical Biochemistry and Genetics, Institute of Biomedicine, University of Turku, and Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland.
authors: Petra
authors: P
authors: Pasanen
authors: Department of Medical Biochemistry and Genetics, Institute of Biomedicine, University of Turku, and Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland.
authors: Maija
authors: M
authors: Siitonen
authors: Department of Pathology, Kuopio University Hospital, Kuopio, Finland.
authors: Jaana
authors: J
authors: Rummukainen
authors: Department of Neurology, Helsinki University Hospital, and Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland.
authors: Pentti J
authors: PJ
authors: Tienari
authors: Department of Pathology, University of Helsinki and HUSLAB, Helsinki, Finland.
authors: Anders
authors: A
authors: Paetau
authors: Department of Pathology, University of Helsinki and HUSLAB, Helsinki, Finland.
authors: Liisa
authors: L
authors: Myllykangas
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000473:pathology*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D005192:Family Health; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D000077153:Progranulins; D012333:RNA, Messenger / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D012333:RNA, Messenger; C000598624:TARDBP protein, human; D014443:Tyrosine
keywords: Frontotemporal dementia; TDP-43; frontotemporal lobar degeneration; mutation; progranulin (GRN)