title: Novel GRN Mutations in Patients with Corticobasal Syndrome.
abstract: Loss-of-function GRN mutations lead to GRN haploinsufficiency and consequently neurodegeneration with significant heterogeneity in clinical presentation of various syndromes. The aim of this study was to investigate the genetics and clinical features of patients with GRN-related frontotemporal lobar degeneration (FTLD) syndromes. We performed mutation analysis of GRN in 45 unrelated Canadian patients with a broad spectrum of FTLD-like syndromes (mean age at onset of 64.0 ± 11.2 years). In our cohort, two patients were carriers of two novel heterozygous alterations in GRN: 2 bp insertion (c.769-770insCC:p.Q257fs) and 12 bp deletion (c.1009-1020del:p.337-340del). Both patients presented with corticobasal syndrome supported by clinical and radiological findings. The absence of the mutant allele in the RT-PCR product was only observed for the sample with 2 bp insertion in GRN. In contrast, the allele with 12 bp deletion in GRN was not down-regulated at the RNA level and did not segregate with FTLD in the family. Our report extends the evidence for genetic and phenotypic variability in FTLD disorders, and detects a novel pathogenic GRN mutation, carriers of which could eventually help to evaluate the efficacy of different treatments at early stages of dementia.
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard avenue, Toronto, ON M5T 2S8, Canada.
authors.forename: Foad
authors.initials: F
authors.lastname: Taghdiri
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard avenue, Toronto, ON M5T 2S8, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Sato
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard avenue, Toronto, ON M5T 2S8, Canada.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Ghani
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard avenue, Toronto, ON M5T 2S8, Canada.
authors.forename: Danielle
authors.initials: D
authors.lastname: Moreno
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard avenue, Toronto, ON M5T 2S8, Canada.|Department of Medicine, Division of Neurology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Rogaeva
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard avenue, Toronto, ON M5T 2S8, Canada.|Devision of Neurology, University Health Network memory clinic, Toronto Western Hospital, 399 Bathurst street, ON M5T 2S8, Canada.
authors.forename: Maria Carmela
authors.initials: MC
authors.lastname: Tartaglia
mesh_terms: D017668:Age of Onset; D000368:Aged; D000483:Alleles; D002170:Canada; D004252:DNA Mutational Analysis; D003704:Dementia / Q000235:genetics* / Q000473:pathology; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional / Q000235:genetics; D000077153:Progranulins; D017384:Sequence Deletion / Q000235:genetics
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins