Journal Article

Mutations in <i>progranulin</i> are a major cause of ubiquitin-positive frontotemporal lobar degeneration

Jennifer Gass, Ashley Cannon, Ian R. Mackenzie, Bradley Boeve, Matt Baker, Jennifer Adamson, Richard Crook, Stacey Melquist, Karen Kuntz, Ron Petersen, Keith Josephs, Stuart M. Pickering-Brown, Neill Graff-Radford, Ryan Uitti, Dennis Dickson, Zbigniew Wszolek, John Gonzalez, Thomas G. Beach, Eileen Bigio, Nancy Johnson, Sandra Weintraub, Marsel Mesulam, Charles L. White, Bryan Woodruff, Richard Caselli, Ging-Yuek Hsiung, Howard Feldman, Dave Knopman, Mike Hutton and Rosa Rademakers

in Human Molecular Genetics

Volume 15, issue 20, pages 2988-3001
Published in print October 2006 | ISSN: 0964-6906
Published online September 2006 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddl241
Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration

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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.

Journal Article.  9669 words.  Illustrated.

Subjects: Genetics and Genomics

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