title: Frontotemporal dementia and parkinsonism associated with the IVS1+1G->A mutation in progranulin: a clinicopathologic study.
abstract: We previously reported a kindred with three cases of dementia, in which the proband exhibited features typical of frontotemporal dementia and parkinsonism (FTDP). An arginine insertion at codon 352 (insR352) in the presenilin-1 (PSEN1) gene was identified in the proband, but analyses in plasma and CSF suggested a mechanism of neurodegeneration not directly related to amyloid pathophysiology. The proband was followed with yearly evaluations of functional, clinical, neuropsychologic, neuropsychiatric and radiologic status, which showed relatively linear change over the initial 4 years of assessment. Upon the proband's death at age 63, neuropathologic examination revealed frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions (FTLD-U). We recently identified several kindreds with familial FTDP associated with mutations in the progranulin (PGRN) gene, particularly in those cases with neuronal intranuclear inclusions. Our proband was indeed found to have such inclusions, and PGRN analysis in this proband revealed the G to A mutation in the exon 1 splice donor site (IVS1+1G-->A) which is predicted to destroy the 5'-splice site of exon 1 and remove the start methionine codon and hence completely block any PGRN protein from being generated. These findings suggest that the insR352 PSEN1 is not pathogenic, and the IVS1+1G-->A mutation in PGRN causes FTDP associated with FTLD-U pathology and represents a new class of neurodegenerative disease--the 'hypoprogranulinopathies'.
authors.affiliation: Department of Neurology, Mayo Clinic Rochester, MN 55905, USA. bboeve@mayo.edu
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.forename: Matt
authors.initials: M
authors.lastname: Baker
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.forename: Caterina
authors.initials: C
authors.lastname: Giannini
authors.forename: Keith A
authors.initials: KA
authors.lastname: Josephs
authors.forename: Michael
authors.initials: M
authors.lastname: Hutton
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pickering-Brown
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: David
authors.initials: D
authors.lastname: Tang-Wai
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.forename: Kejal
authors.initials: K
authors.lastname: Kantarci
authors.forename: Maria M
authors.initials: MM
authors.lastname: Shiung
authors.forename: Todd
authors.initials: T
authors.lastname: Golde
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Smith
authors.forename: Yonas E
authors.initials: YE
authors.lastname: Geda
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
mesh_terms: D001931:Brain Mapping / Q000379:methods; D003704:Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017809:Fatal Outcome; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D045586:Intranuclear Inclusion Bodies / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008875:Middle Aged; D009154:Mutation; D009483:Neuropsychological Tests; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077153:Progranulins; D011569:Psychiatric Status Rating Scales; D012720:Severity of Illness Index; D025801:Ubiquitin / Q000378:metabolism
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D025801:Ubiquitin