The MAPT p.A152T variant is a risk factor associated with tauopathies with atypical clinical and neuropathological features

Abstract

Microtubule-associated protein tau (MAPT) mutations have been shown to underlie frontotemporal dementia and a variety of additional sporadic tauopathies. We identified a rare p.A152T variant in MAPT exon 7 in two (of eight) patients with clinical presentation of parkinsonism and postmortem finding of neurofibrillary tangle pathology. Two siblings of one patient also carried the p.A152T variant, and both have progressive cognitive impairment. Further screening identified the variant in two other cases: one with pathologically confirmed corticobasal degeneration and another with the diagnosis of Parkinson's disease with dementia. The balance of evidence suggests this variant is associated with disease, but the very varied phenotype of the cases with the mutation is not consistent with it being a fully penetrant pathogenic mutation. Interestingly, this variation results in the creation of a new phosphorylation site that could cause reduced microtubule binding. We suggest that the A152T variant is a risk factor associated with the development of atypical neurodegenerative conditions with abnormal tau accumulation.

Stabilizing the Hsp70-Tau Complex Promotes Turnover in Models of Tauopathy

“…the pool that is not bound to microtubules) is considered to be most likely to aggregate. Indeed, mutations, such as P301L and A152T (Coppola et al, 2012; Hong et al, 1998; Kara et al, 2012; Vogelsberg-Ragaglia et al, 2000), and/or post-translational modifications (PTMs), such as hyperphosphorylation and acetylation (Cook et al, 2014; Hanger et al, 2009; Morris et al, 2015), seem to disrupt the affinity of tau for microtubules and promote its aggregation.…”

Pearls & Oy-sters: Ocular motor apraxia as essential differential diagnosis to supranuclear gaze palsy

“…The identified p.A152T MAPT variant predisposes for tauopathies, including PSP and CBD, associated with a CSF biomarker pattern as in our patient. 6,7 Consistently, [ 18 F]-AV-1451 PET suggested tau pathology with the highest 12-month progression rate in the right-sided parietal and insular cortex, and bilaterally in the striatum. This asymmetric corticobasal ganglionic pattern is most likely caused by CBD pathology, but PSP pathology also can cause such a pattern and cannot be ruled out with certainty in our patient.…”

“…However, the rare p.A152T variant was found in MAPT, which has been described as a risk factor for tauopathies. 6,7 Structural MRI confirmed mild right-sided parietal cortical atrophy (figure, E). PET with the tau-binding tracer […”

O4‐01‐04: Amyloid in Dementia Associated With Familial Ftld: Not an Innocent Bystander

“…p.A152T has been associated with increased formation of tau oligomers and inefficient microtubule assembly , and with fragmentation and hyperphosphorylation of tau and neurodegeneration in induced pluripotent stem cells (Fong et al, 2013). Most p.A152T cases with autopsy have had tauopathies with low levels of amyloid (Kara et al, 2012;Kovacs et al, 2011). A simple interpretation of these findings would be to conclude that our A+ with this variant simply has AD; however, considering this case in light of the others in our analysis requires a more complex interpretation.…”