Phenotypic heterogeneity within a new family with the MAPT p301s mutation

Abstract

Mutations in the gene encoding the microtubule-associated protein tau (MAPT) cause frontotemporal dementia and parkinsonism linked to chromosome 17. Clinical variability is seen not only among families with different mutations, but also among family members with the same mutation. We investigated a newly identified familial frontotemporal dementia and parkinsonism family. The disease was of early onset and was inherited as an autosomal dominant trait. Clinically, parkinsonism was the prominent and often early feature, and it preceded dementia. Three autopsied cases shared involvement predominantly in the frontal and temporal lobes and also in the subcortical nuclei, including substantia nigra, globus pallidus, and subthalamic nucleus, that microscopically consisted of neuronal loss, microvacuolation, and astrocytic fibrosis. Immunohistochemistry demonstrated neuropil threads, ballooned cells, and glial fibrillary tangles. Sequencing analysis of the MAPT gene showed an alteration in one allele, resulting in a P301S substitution. These findings suggest that the MAPT P301S mutation can cause pathologically subcortical-predominant, neuropil thread-rich, tau-containing lesions, which could result in consistent parkinsonism. Our study confirms the notion that the phenotype observed in affected individuals from P301S MAPT mutation families is heterogeneous and is broader than the phenotypes seen to date in affected family members carrying other MAPT mutations.

Invited review: Frontotemporal dementia caused by microtubule‐associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging

“…Figure shows the 53 mutations that are currently known [6–9,14,16,33,34,38,39,47–132]. The most common are N279K, P301L and intron 10 +16 .…”

The CNS in inbred transgenic models of 4-repeat Tauopathy develops consistent tau seeding capacity yet focal and diverse patterns of protein deposition

“…Hence a more pertinent question is “how can heterogeneity occur in aged brains, given the genetic constraints, the absence of extraneous pathogens and the regulated housing conditions?”. While the performance of other mouse models with indolent Tau deposition remains to be assessed, the question about heterogeneity is underscored by the benchmark of human case material, where phenotypic variation exists in human FTDP-17 MAPT kindreds, and can be present even within families harboring the exact same mutation in codon 301 [ 1 , 14 , 15 , 17 , 76 – 78 ].…”

Conditionally inducible tau mice – designing a better mouse model of neurodegenerative diseases

“…Of eight THY‐Tau generated lines, five expressed low levels of tau and were excluded, one line expressed high level of tau in a spinal cord leading to its exclusion and one line showed low levels of tau in the hippocampus (HP) and cortex with very late (>18 months) onset of tau pathology and was also excluded (Schindowski et al 2006). Second, the model overexpresses two tau mutations, P301S implicated in the family of FTPs and CBD (Yasuda et al 2005) and G272V mutation leading to tau pathology similar to that of FTD and PiD (Bronner et al 2005; Gotz et al 2001; Rosso et al 2003). Therefore, this model is relevant to classical tauopathy, but it is of less interest to AD in terms of construct validity as no known tau mutations or polymorphism have been associated with this disease.…”