Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative - 16/08/11

Doi : 10.1016/S1474-4422(07)70221-1

Rosa Rademakers, PhD ^a,^⁎ , Matt Baker, BSc ^a, Jennifer Gass, BS ^a, Jennifer Adamson, BS ^a, Edward D Huey, MD ^b, Parastoo Momeni, PhD ^c, Salvatore Spina, MD ^d,^e, Giovanni Coppola, MD ^f, Anna M Karydas, BA ^g, Heather Stewart, PhD ^h, Nancy Johnson, PhD ⁱ, Ging-Yuek Hsiung, MD ^j, Brendan Kelley, MD ^k, Karen Kuntz, RN ^k, Ellen Steinbart, MA ^l, Elisabeth McCarty Wood, MS ^m, Chang-En Yu, PhD ⁿ, Keith Josephs, MD ^k, Eric Sorenson, MD ^k, Kyle B Womack, MD ^o, Sandra Weintraub, PhD ⁱ, Stuart M Pickering-Brown, PhD ^p, Peter R Schofield, DSc ^q, William S Brooks, MBBS ^q, Vivianna M Van Deerlin, MD ^m, Julie Snowden, PhD ^p, Christopher M Clark, MD ^r, Andrew Kertesz, MD ^s, Kevin Boylan, MD ^t, Bernardino Ghetti, MD ^d, David Neary, FRCP ^p, Gerard D Schellenberg, PhD ⁿ, Thomas G Beach, FRCPC ^u, Marsel Mesulam, MD ⁱ, David Mann, PhD ^p, Jordan Grafman, PhD ^b, Ian R Mackenzie, MD ^v, Howard Feldman, MD ^j, Thomas Bird, MD ^l, Ron Petersen, MD ^k, David Knopman, MD ^k, Bradley Boeve, MD ^k, Dan H Geschwind, MD ^f, Bruce Miller, MD ^g, Zbigniew Wszolek, MD ^t, Carol Lippa, MD ^w, Eileen H Bigio, MD ⁱ, Dennis Dickson, MD ^a, Neill Graff-Radford, FRCP ^t, Mike Hutton, PhD ^a

^a Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA

^b Cognitive Neuroscience Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

^c Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX, USA

^d Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

^e Department of Neurological and Behavioral Sciences, University of Siena, Siena, Italy

^f Department of Neurology, The David Geffen School of Medicine at University of California, Los Angeles, CA, USA

^g Department of Neurology, University of California, San Francisco, CA, USA

^h The ALS Centre, Vancouver General Hospital, Vancouver, BC, Canada

ⁱ Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

^j Division of Neurology, University of British Columbia, Vancouver, BC, Canada

^k Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA

^l Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA

^m Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

ⁿ 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, USA

^o Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA

^p School of Translational Medicine, Faculty of Medical and Health Sciences, University of Manchester, Manchester, UK

^q Prince of Wales Medical Research Institute and University of New South Wales, Sydney, NSW, Australia

^r Alzheimer’s Disease Center, Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

^s University of Western Ontario, London, ON, Canada

^t Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL, USA

^u Sun Health Research Institute, Sun City, AZ, USA

^v Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

^w Department of Neurology, Drexel University College of Medicine, Philadelphia, PA, USA

^* Correspondence to: Rosa Rademakers, Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA

Summary

Background

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.

Methods

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).

Findings

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 4 allele.

Interpretation

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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Vol 6 - N° 10

P. 857-868 - octobre 2007 Retour au numéro

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Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative - 16/08/11

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