TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers
- 1 February 2011
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Neurology
- Vol. 76 (5), 467-474
- https://doi.org/10.1212/wnl.0b013e31820a0e3b
Abstract
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, pallelic = 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected pallelic = 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 precessive = 0.009). We further identified a significant association of TMEM106B SNPs with plasma GRN levels in controls (top SNP rs1990622, corrected p = 0.002) and in peripheral blood samples a highly significant correlation was observed between TMEM106B and GRN mRNA expression in patients with FTLD (r = −0.63, p = 7.7 × 10−5) and controls (r = −0.49, p = 2.2 × 10−10). 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.Keywords
This publication has 26 references indexed in Scilit:
- Accelerated Lipofuscinosis and Ubiquitination in Granulin Knockout Mice Suggest a Role for Progranulin in Successful AgingThe American Journal of Pathology, 2010
- Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusionsNature Genetics, 2010
- Prediction of pathology in primary progressive language and speech disordersNeurology, 2010
- Loss of progranulin function in frontotemporal lobar degenerationTrends in Genetics, 2008
- The genetics of frontotemporal lobar degeneration.Current Neurology and Neuroscience Reports, 2007
- The molecular genetics and neuropathology of frontotemporal lobar degeneration: recent developmentsneurogenetics, 2007
- Clinicopathological correlates in frontotemporal dementiaAnnals of Neurology, 2004
- Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesisJournal of Molecular Medicine, 2003
- Conversion of Proepithelin to Epithelins: Roles of SLPI and Elastase in Host Defense and Wound RepairCell, 2002
- Clinical and Pathological Diagnosis of Frontotemporal DementiaArchives of Neurology, 2001