Journal article
Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative
Lancet neurology, v 6(10), pp 857-868
2007
PMID: 17826340
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The progranulin gene (
GRN) is mutated in 5–10% of patients with frontotemporal lobar degeneration (FTLD) and in about 20% of patients with familial FTLD. The most common mutation in
GRN is Arg493X. We aimed to establish the contribution of this mutation to FTLD and related disorders.
We measured the frequency of Arg493X in 3405 unrelated patients with various neurodegenerative diseases using Taqman single-nucleotide polymorphism (SNP) genotyping. Clinicopathological characterisation and shared haplotype analysis were done for 30 families with FTLD who carry Arg493X. To investigate the effect of potential modifying loci, we did linear regression analyses with onset age as the covariate for
GRN variants, for genotypes of the apolipoprotein E gene (
APOE), and for haplotypes of the microtubule-associated protein tau gene (
MAPT).
Of 731 patients with FTLD, 16 (2%) carried Arg493X. This mutation was not detected in 2674 patients who did not have FTLD. In 37 patients with Arg493X from 30 families with FTLD, clinical diagnoses included frontotemporal dementia, primary progressive aphasia, corticobasal syndrome, and Alzheimer's disease. Range of onset age was 44–69 years. In all patients who came to autopsy (n=13), the pathological diagnosis was FTLD with neuronal inclusions that contained TAR DNA-binding protein or ubiquitin, but not tau. Neurofibrillary tangle pathology in the form of Braak staging correlated with overall neuropathology in the Arg493X carriers. Haplotype analyses suggested that Arg493X arose twice, with a single founder for 27 families. Linear regression analyses suggested that patients with SNP rs9897528 on their wild-type
GRN allele have delayed symptom onset. Onset ages were not associated with the
MAPT H1 or H2 haplotypes or
APOE genotypes, but early memory deficits were associated with the presence of an
APOE ɛ4 allele.
Clinical heterogeneity is associated with
GRN haploinsufficiency, and genetic variability on the wild-type
GRN allele might have a role in the age-related disease penetrance of
GRN mutations.
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Details
- Title
- Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative
- Creators
- Rosa Rademakers - Mayo ClinicMatt Baker - Mayo ClinicJennifer Gass - Mayo ClinicJennifer Adamson - Mayo ClinicEdward D Huey - National Institutes of HealthParastoo Momeni - Texas Tech University Health Sciences CenterSalvatore Spina - Indiana UniversityGiovanni Coppola - University of California, Los AngelesAnna M Karydas - University of California, San FranciscoHeather Stewart - University of British ColumbiaNancy Johnson - Northwestern UniversityGing-Yuek Hsiung - University of British ColumbiaBrendan Kelley - Mayo ClinicKaren Kuntz - Mayo ClinicEllen Steinbart - University of WashingtonElisabeth McCarty Wood - Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USAChang-En Yu - Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, and Departments of Medicine, Neurology, and Pharmacology, University of Washington, Seattle, WA, USAKeith Josephs - Mayo ClinicEric Sorenson - Mayo ClinicKyle B Womack - The University of Texas Southwestern Medical CenterSandra Weintraub - Northwestern UniversityStuart M Pickering-Brown - University of ManchesterPeter R Schofield - UNSW SydneyWilliam S Brooks - UNSW SydneyVivianna M Van Deerlin - Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USAJulie Snowden - University of ManchesterChristopher M Clark - University of PennsylvaniaAndrew Kertesz - Western UniversityKevin Boylan - Mayo ClinicBernardino Ghetti - Indiana UniversityDavid Neary - University of ManchesterGerard D Schellenberg - Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, and Departments of Medicine, Neurology, and Pharmacology, University of Washington, Seattle, WA, USAThomas G Beach - Sun Health Research Institute, Sun City, AZ, USAMarsel Mesulam - Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USADavid Mann - School of Translational Medicine, Faculty of Medical and Health Sciences, University of Manchester, Manchester, UKJordan Grafman - National Institutes of HealthIan R Mackenzie - University of British ColumbiaHoward Feldman - University of British ColumbiaThomas Bird - University of WashingtonRon Petersen - Mayo ClinicDavid Knopman - Mayo ClinicBradley Boeve - Mayo ClinicDan H Geschwind - Department of Neurology, The David Geffen School of Medicine at University of California, Los Angeles, CA, USABruce Miller - University of California, San FranciscoZbigniew Wszolek - Mayo ClinicCarol Lippa - Drexel UniversityEileen H Bigio - Northwestern UniversityDennis Dickson - Mayo ClinicNeill Graff-Radford - Mayo ClinicMike Hutton - Mayo Clinic
- Publication Details
- Lancet neurology, v 6(10), pp 857-868
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Web of Science ID
- WOS:000250035600016
- Scopus ID
- 2-s2.0-34548633862
- Other Identifier
- 991019312445104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Clinical Neurology