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


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.

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@article{Gass2006MutationsIP, title={Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration.}, author={Jennifer M Gass and Ashley Cannon and Ian R Mackenzie and Bradley F. Boeve and Matt C Baker and Jennifer L. Adamson and Richard J. P. Crook and Stacey Melquist and Karen M. Kuntz and R. C. Petersen and Keith A. Josephs and Stuart M. Pickering-Brown and Neill R. Graff-Radford and Ryan J. Uitti and Dennis W Dickson and Zbigniew K Wszolek and John Gonzalez and Thomas Beach and Eileen Bigio and Nancy A Johnson and Sandra Weintraub and Marsel M. Mesulam and Charles L. White and B K Woodruff and Richard J. Caselli and Ging-Yuek R Hsiung and Howard H . Feldman and Dave Knopman and Mike Hutton and Rosa Rademakers}, journal={Human molecular genetics}, year={2006}, volume={15 20}, pages={2988-3001} }