Human Molecular Genetics Advance Access published online on September 1, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl241
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1 Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville FL 32224
* To whom correspondence should be addressed. Null mutations in the progranulin gene (PGRN) were recently reported to cause tau-negative frontotemporal dementia (FTD) 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 that 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 8 independently ascertained familial FTLD patients that 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 (FTLD-U) in all PGRN mutation carriers.
Received August 19, 2006
Accepted August 30, 2006
Article
Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration
Jennifer Gass 1, Ashley Cannon 1, Ian R. Mackenzie 2, Bradley Boeve 3, Matt Baker 1, Jennifer Adamson 1, Richard Crook 1, Stacey Melquist 1, Karen Kuntz 3, Ron Petersen 3, Keith Josephs 3, Stuart-Pickering Brown 4, Neill Graff-Radford 5, Ryan Uitti 5, Dennis Dickson 1, Zbigniew Wzsolek 5, John Gonzalez 1, Thomas G. Beach 6, Eileen Bigio 7, Nancy Johnson 7, Sandra Weintraub 7, Marsel Mesulam 7, Charles L. White III 8, Bryan Woodruff 9, Richard Caselli 9, Ging-Yuek Hsiung 10, Howard Feldman 10, Dave Knopman 3, Mike Hutton 1 *, and Rosa Rademakers 1
2 Department of Pathology, University of British Columbia, Vancouver, Canada
3 Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA
4 Division of Laboratory and Regenerative Medicine, Department of Medicine, University of Manchester, Manchester, UK
5 Department of Neurology, Mayo Clinic College of Medicine, Jacksonville FL, USA
6 Sun Health Research Institute, Sun City, AZ, USA
7 Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
8 Neuropathology Division, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX, USA
9 Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA
10 Division of Neurology, University of British Columbia, Vancouver, Canada
Mike Hutton, E-mail: hutton.Michael{at}mayo.edu
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