| Title |
TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia
|
|---|---|
| Published in |
Acta Neuropathologica, January 2014
|
| DOI | 10.1007/s00401-013-1240-4 |
| Pubmed ID | |
| Authors |
Marka van Blitterswijk, Bianca Mullen, Alexandra M. Nicholson, Kevin F. Bieniek, Michael G. Heckman, Matthew C. Baker, Mariely DeJesus-Hernandez, NiCole A. Finch, Patricia H. Brown, Melissa E. Murray, Ging-Yuek R. Hsiung, Heather Stewart, Anna M. Karydas, Elizabeth Finger, Andrew Kertesz, Eileen H. Bigio, Sandra Weintraub, Marsel Mesulam, Kimmo J. Hatanpaa, Charles L. White III, Michael J. Strong, Thomas G. Beach, Zbigniew K. Wszolek, Carol Lippa, Richard Caselli, Leonard Petrucelli, Keith A. Josephs, Joseph E. Parisi, David S. Knopman, Ronald C. Petersen, Ian R. Mackenzie, William W. Seeley, Lea T. Grinberg, Bruce L. Miller, Kevin B. Boylan, Neill R. Graff-Radford, Bradley F. Boeve, Dennis W. Dickson, Rosa Rademakers |
| Abstract |
Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions [with or without motor neuron disease (MND); cohort 2], and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls [11.9 vs. 19.1 %, odds ratio (OR) 0.57, p = 0.014; same direction as carriers of GRN mutations]. The strongest evidence was provided by FTD patients (OR 0.33, p = 0.009) followed by FTD/MND patients (OR 0.38, p = 0.017), whereas no significant difference was observed in MND patients (OR 0.85, p = 0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR 0.77, p = 0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR 0.26, p < 0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP. |
X Demographics
The data shown below were collected from the profiles of 3 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 3 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 3 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 163 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United Kingdom | 2 | 1% |
| Colombia | 1 | <1% |
| Brazil | 1 | <1% |
| Spain | 1 | <1% |
| United States | 1 | <1% |
| Philippines | 1 | <1% |
| Unknown | 156 | 96% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 31 | 19% |
| Researcher | 29 | 18% |
| Other | 16 | 10% |
| Student > Master | 13 | 8% |
| Student > Doctoral Student | 12 | 7% |
| Other | 32 | 20% |
| Unknown | 30 | 18% |
| Readers by discipline | Count | As % |
|---|---|---|
| Neuroscience | 36 | 22% |
| Medicine and Dentistry | 31 | 19% |
| Agricultural and Biological Sciences | 23 | 14% |
| Biochemistry, Genetics and Molecular Biology | 20 | 12% |
| Computer Science | 3 | 2% |
| Other | 10 | 6% |
| Unknown | 40 | 25% |
Attention Score in Context
This research output has an Altmetric Attention Score of 23. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 30 January 2024.
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#1,483,077
of 23,555,482 outputs
Outputs from Acta Neuropathologica
#275
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Outputs of similar age
#17,490
of 308,398 outputs
Outputs of similar age from Acta Neuropathologica
#4
of 36 outputs
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