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Human Molecular Genetics Advance Access originally published online on September 1, 2006
Human Molecular Genetics 2006 15(20):2988-3001; doi:10.1093/hmg/ddl241
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration

Jennifer Gass1,{dagger}, Ashley Cannon1,{dagger}, Ian R. Mackenzie2, Bradley Boeve4, Matt Baker1, Jennifer Adamson1, Richard Crook1, Stacey Melquist1, Karen Kuntz4, Ron Petersen4, Keith Josephs4, Stuart M. Pickering-Brown5, Neill Graff-Radford6, Ryan Uitti6, Dennis Dickson1, Zbigniew Wszolek6, John Gonzalez1, Thomas G. Beach7, Eileen Bigio8, Nancy Johnson8, Sandra Weintraub8, Marsel Mesulam8, Charles L. White, III9, Bryan Woodruff10, Richard Caselli10, Ging-Yuek Hsiung3, Howard Feldman3, Dave Knopman4, Mike Hutton1,* and Rosa Rademakers1

1 Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA, 2 Department of Pathology , 3 Division of Neurology, University of British Columbia, Vancouver, Canada, 4 Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA, 5 Division of Laboratory and Regenerative Medicine, Department of Medicine, University of Manchester, Manchester, UK, 6 Department of Neurology, Mayo Clinic College of Medicine, Jacksonville FL, USA, 7 Sun Health Research Institute, Sun City, AZ, USA, 8 Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, 9 Neuropathology Division, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX, USA and 10 Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA

* To whom correspondence should be addressed. Tel: +1 9049530159; Fax: +1 9049537370; Email: hutton.michael{at}mayo.edu

Received August 19, 2006; Accepted August 30, 2006

Null mutations in the progranulin gene (PGRN) were recently reported to cause tau-negative frontotemporal dementia linked to chromosome 17. We assessed the genetic contribution of PGRN mutations in an extended population of patients with frontotemporal lobar degeneration (FTLD) (N=378). Mutations were identified in 10% of the total FTLD population and 23% of patients with a positive family history. This mutation frequency dropped to 5% when analysis was restricted to an unbiased FTLD subpopulation (N=167) derived from patients referred to Alzheimer's Disease Research Centers (ADRC). Among the ADRC patients, PGRN mutations were equally frequent as mutations in the tau gene (MAPT). We identified 23 different pathogenic PGRN mutations, including a total of 21 nonsense, frameshift and splice-site mutations that cause premature termination of the coding sequence and degradation of the mutant RNA by nonsense-mediated decay. We also observed an unusual splice-site mutation in the exon 1 5' splice site, which leads to loss of the Kozac sequence, and a missense mutation in the hydrophobic core of the PGRN signal peptide. Both mutations revealed novel mechanisms that result in loss of functional PGRN. One mutation, c.1477C>T (p.Arg493X), was detected in eight independently ascertained familial FTLD patients who were shown to share a common extended haplotype over the PGRN genomic region. Clinical examination of patients with PGRN mutations revealed highly variable onset ages with language dysfunction as a common presenting symptom. Neuropathological examination showed FTLD with ubiquitin-positive cytoplasmic and intranuclear inclusions in all PGRN mutation carriers.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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