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TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers
Journal article   Open access   Peer reviewed

TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers

N. Finch, M. M. Carrasquillo, M. Baker, N. J. Rutherford, G. Coppola, M. DeJesus-Hernandez, R. Crook, T. Hunter, R. Ghidoni, L. Benussi, …
Neurology, v 76(5), pp 467-474
01 Feb 2011
DOI: https://doi.org/10.1212/WNL.0b013e31820a0e3b
PMID: 21178100
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1212/wnl.0b013e31820a0e3bView
Published, Version of Record (VoR)Open Access (License Unspecified),  Open
url
https://doi.org/10.1212/WNL.0b013e31820a0e3bView
Published, Version of Record (VoR) Open

Abstract

Clinical Neurology Life Sciences & Biomedicine Neurosciences & Neurology Science & Technology
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) = 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) = 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) = 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 x 10(-5)) and controls (r = -0.49, p = 2.2 x 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. Neurology (R) 2011;76:467-474

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Web of Science research areas
Clinical Neurology
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