Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimers diseases

Department of Neurology, University of California, Los Angeles, CA, USA.
Human Molecular Genetics (Impact Factor: 6.39). 05/2012; 21(15):3500-12. DOI: 10.1093/hmg/dds161
Source: PubMed


Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.

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Available from: Bernardino Francesco Ghetti, Dec 10, 2015
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    • "The possibility of multiple mutations contributing to ALS in one individual,12 and the role of rare variants in complex diseases such as ALS and FTD, remains to be elucidated and will require very large cohorts in order to obtain sufficiently convincing results. Recently, Geschwind and collaborators have shown that a rare variant in the MAPT gene, where mutations are known to be causative for FTD, can act as a risk factor for FTD and Alzheimer's disease.13 Similarly, we here suggest that a rare variant in PFN1, a gene in which mutations are known to be causative for ALS, can act as a risk factor for disease. "
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    • "There was also immunoreactivity in a subset of Lewy bodies, similar to the pattern we previously noted with other antibodies to phospho-tau [30]. T149 and T153 are largely unexplored tau epitopes, but it is of interest that they flank a rare variant in tau, A152T, that may be a risk factor for tauopathies such as PSP [7, 34, 36]. LRRK2 is not known to play a role in tauopathies beyond its involvement in PD, but it is possible that rare genetic variants in LRRK2, including those that confer risk to PD [16, 60, 62] or have yet to be uncovered, could play a role in tauopathies. "
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    • "The novel MAPT variant identified in our case is located in a region of the protein far from microtubule-binding domains and does not have an obvious role in the molecule's function. A similar variant was also recently reported in exon 7 of the MAPT gene (Coppola et al., 2012; Cruchaga et al., 2012; Jin et al., 2012; Kara et al., 2012), and a rare variant p.A239T in exon 8 (NM_005910.5) was found in a carrier of a C9orf72 repeat expansion (King et al., 2013) (Fig. 1). Interestingly, these 3 rare variants all localize in an uncharacterized region of the MAPT protein in cases with unexpected tau pathology, which supports the speculation that these variants may have a disease-modifying role and may predispose the individual to tau pathology (Coppola et al., 2012; Devine and Lewis, 2008; Gan-Or et al., 2012; Kara et al., 2012). "
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