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.

Objectives: To determine whether TMEM106B single nucleotide polymorphisms (SNPs) are associated with frontotemporal lobar degeneration (FTLD) in patients with and without mutations in progranulin (GRN) and to determine whether TMEM106B modulates GRN expression. Methods:We performed a case-control study of 3 SNPs in TMEM106B in 482 patients with clinical and 80 patients with pathologic FTLD-TAR DNA-binding protein 43 without GRN mutations, 78 patients with FTLD with GRN mutations, and 822 controls. Association analysis of TMEM106B with GRN plasma levels was performed in 1,013 controls and TMEM106B and GRN mRNA expression levels were correlated in peripheral blood samples from 33 patients with FTLD and 150 controls. Results:In our complete FTLD patient cohort, nominal significance was identified for 2 TMEM106B SNPs (top SNP rs1990622, p allelic ϭ 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected p allelic ϭ 0.0009), where there was a highly significant decrease in the frequency of homozygote carriers of the minor alleles of all TMEM106B SNPs (top SNP rs1990622, CC genotype frequency 2.6% vs 19.1%, corrected p recessive ϭ 0.009). We further identified a significant association of TMEM106B SNPs with plasma GRN levels in controls (top SNP rs1990622, corrected p ϭ 0.002) and in peripheral blood samples a highly significant correlation was observed between TMEM106B and GRN mRNA expression in patients with FTLD (r ϭ Ϫ0.63, p ϭ 7.7 ϫ 10 Ϫ5 ) and controls (r ϭ Ϫ0.49, p ϭ 2.2 ϫ 10 Ϫ10 ). Conclusions:In our study, TMEM106B SNPs significantly reduced the disease penetrance in patients with GRN mutations, potentially by modulating GRN levels. These findings hold promise for the development of future protective therapies for FTLD. Neurology Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder accounting for 5%-10% of all patients with dementia and 10%-20% of patients with dementia with an onset before age 65 years. 1,2 In recent years, major advances have been made in our understanding of both the neuropathologic and genetic bases of FTLD.3 Mutations in the genes encoding the microtubule-associated protein tau (MAPT) 4-6 and progranulin (GRN) 7,8 together explain 10%-25% of familial FTLD and 5%-10% of all FTLD cases.9 While patients with MAPT e-Pub ahead of print on December 22, 2010, at www.neurology.org *These authors contributed equally to this work.From the Departments of Neuroscience (N.F., M.M.C., M.B., N