| First Author | Cabron AS | Year | 2023 |
| Journal | Acta Neuropathol Commun | Volume | 11 |
| Issue | 1 | Pages | 21 |
| PubMed ID | 36707901 | Mgi Jnum | J:336032 |
| Mgi Id | MGI:7431539 | Doi | 10.1186/s40478-023-01510-3 |
| Citation | Cabron AS, et al. (2023) Lack of a protective effect of the Tmem106b "protective SNP" in the Grn knockout mouse model for frontotemporal lobar degeneration. Acta Neuropathol Commun 11(1):21 |
| abstractText | Genetic variants in TMEM106B are a common risk factor for frontotemporal lobar degeneration and the most important modifier of disease risk in patients with progranulin (GRN) mutations (FTLD-GRN). TMEM106B is encoding a lysosomal transmembrane protein of unknown molecular function. How it mediates its disease-modifying function remains enigmatic. Several TMEM106B single nucleotide polymorphisms (SNPs) are significantly associated with disease risk in FTLD-GRN carriers, of which all except one are within intronic sequences of TMEM106B. Of note, the non-coding SNPs are in high linkage disequilibrium with the coding SNP rs3173615 located in exon six of TMEM106B, resulting in a threonine to serine change at amino acid 185 in the minor allele, which is protective in FTLD-GRN carriers. To investigate the functional consequences of this variant in vivo, we generated and characterized a knockin mouse model harboring the Tmem106b(T186S) variant. We analyzed the effect of this protective variant on FTLD pathology by crossing Tmem106b(T186S) mice with Grn(-/-) knockout mice, a model for GRN-mediated FTLD. We did not observe the amelioration of any of the investigated Grn(-/-) knockout phenotypes, including transcriptomic changes, lipid alterations, or microgliosis in Tmem106b(T186S/T186S) x Grn(-/-) mice, indicating that the Tmem106b(T186S) variant is not protective in the Grn(-/-) knockout mouse model. These data suggest that effects of the associated SNPs not directly linked to the amino acid exchange in TMEM106B are critical for the modifying effect. |
