Elsevier

Neurobiology of Aging

Volume 35, Issue 2, February 2014, Pages 408-417
Neurobiology of Aging

Regular article
Different mutations at V363 MAPT codon are associated with atypical clinical phenotypes and show unusual structural and functional features

https://doi.org/10.1016/j.neurobiolaging.2013.08.004Get rights and content

Abstract

Microtubule-associated protein tau gene (MAPT) is one of the major genes linked to frontotemporal lobar degeneration, a group of neurodegenerative diseases clinically, pathologically, and genetically heterogeneous. In particular, MAPT mutations give rise to the subgroup of tauopathies. The pathogenetic mechanisms underlying the MAPT mutations so far described are the decreased ability of tau protein to promote microtubule polymerization (missense mutations) or the altered ratio of tau isoforms (splicing mutations), both leading to accumulation of hyperphosphorylated filamentous tau protein. Following a genetic screening of patients affected by frontotemporal lobar degeneration, we identified 2 MAPT mutations, V363I and V363A, leading to atypical clinical phenotypes, such as posterior cortical atrophy. We investigated in vitro features of the recombinant mutated tau isoforms and revealed unusual functional and structural characteristics such as an increased ability to promote microtubule polymerization and a tendency to form oligomeric instead of filamentous aggregates. Thus, we disclosed a greater than expected complexity of abnormal features of mutated tau isoforms. Overall our findings suggest a high probability that these mutations are pathogenic.

Introduction

Frontotemporal lobar degeneration (FTLD) is a form of dementia clinically characterized by changes in behavior/personality and impairment of language. Behavioral variant of frontotemporal dementia (bvFTD), progressive nonfluent aphasia (PNFA), and semantic dementia are the major clinical phenotypes associated with FTLD. Parkinsonism and, less frequently, motor neuron disease, also can be present, resulting in progressive supranuclear palsy (PSP)-like phenotype, corticobasal syndrome (CBS), and FTLD-motor neuron disease (Espay and Litvan, 2011, Seelaar et al., 2011).

FTLD is genetically heterogeneous, and 3 genes are responsible for the majority of familial cases: microtubule-associated protein tau gene (MAPT), gene coding for progranulin (GRN), and chromosome 9 open reading frame 72 gene (C9ORF72). Mutations in valosin-containing protein (VCP) and charged multivescicular body protein 2B (CHMP2B) genes are more rare, and mutations in TAR DNA binding protein 43 (TDP43) and fused in sarcoma (FUS) genes have been detected in a very limited number of cases (Majounie et al., 2012, Seelaar et al., 2011).

From the neuropathologic point of view, MAPT mutations invariably cause filamentous tau deposits in neuronal and glial cells (Goedert and Spillantini, 2011), whereas TDP43 deposits are the hallmark of the mutations in the other genes, with some exceptions (CHMP2B and FUS) (Seelaar et al., 2011) and peculiarities (cases carrying the C9ORF72 expansion have additional deposits of dipeptide-repeat proteins) (Ash et al., 2013, Mori et al., 2013).

A tight correlation between genotype and clinical phenotype cannot be predicted, either intragene or intergene. However, some preferential associations have been reported (Rohrer and Warren, 2011). For instance, PNFA is associated more frequently with GRN mutations, as these have been found in up to1/3 of PNFA cases (Pickering-Brown et al., 2008), whereas it has been described only in two cases carrying a MAPT mutation (Munoz et al., 2007, Villa et al., 2011). PSP-like phenotypes are associated with MAPT mutations (Rohrer and Warren, 2011).

Mutations in MAPT are pathogenic based on two different mechanisms: missense mutations reduce the physiological function of tau, the ability to promote microtubule polymerization, whereas splicing mutations alter the normal ratio between isoforms bearing 3 or 4 repeats (3R and 4R, respectively) in the microtubule-binding domain (MBD), leading in both cases to aggregates of insoluble filaments of tau. Most of the mutations in MAPT are clustered in the exons 9–12, coding for the repeats of the MBD, and in the intron 10. Nearly all the missense mutations in the MBD were demonstrated to be pathogenic by either segregation analysis or neuropathologic examination or, alternatively, their abnormal features were characterized by in vitro functional studies, suggesting the importance of this domain for the protein function. Some mutations were not actually proven but supposed to be pathogenic due to their position near (G273R, G304S) or at the same codon (L284R, P301T) where other pathogenic mutations had been described. Still controversial are the V300I and V363I mutations. However, V300I was reported in the DNA from a non characterized control subject who may have been a presymptomatic carrier (Guerreiro et al., 2010a), and V363I was described both in affected and asymptomatic subjects suggesting the possibility of incomplete penetrance (Anfossi et al., 2011, Bessi et al., 2010, Munoz et al., 2007).

In this study we report the clinical description of two unrelated patients carrying the V363I mutation, showing atypical presentations of PNFA and posterior cortical atrophy (PCA), and a patient carrying the novel V363A mutation presenting as PSP. Thus, surprisingly different phenotypes were associated with mutations at the same MAPT codon. In addition, we analyzed the mutated tau isoforms by in vitro assays to gain insight into their pathological features. The mutated tau isoforms showed unusual and abnormal features strongly suggesting their pathogenicity.

Section snippets

Methods

In this study, we did not perform any experimental treatment on human subjects. The informed consent to genetic analysis for diagnostic and research purposes was obtained from all subjects, and the Institutional Review Board of Neurological Institute “Carlo Besta” was notified about this study. The Institutional Review Board considered this satisfactory and did not require further evaluation for the study.

Italian patients affected by FTLD (n = 104; age of onset: range, 36–80 years; mean ± SD,

Genetic analysis

Sequence analysis (Fig. 1) of MAPT revealed the GTC to ATC base change at codon 363, resulting in isoleucine for valine substitution (V363I), in patients 1 and 2, and the GTC to GCC change, resulting in alanine for valine substitution (V363A), in patient 3 (441-amino acids tau isoform, Reference Sequence NP_005901.2, National Center for Biotechnology Information). The mutations were absent in the mother of patient 3, the 100 healthy subjects and 300 non-FTLD neurological patients. All the

Discussion

We describe here three patients carrying different mutations at the same MAPT codon, who showed very different and atypical clinical phenotypes. PNFA, which includes AOS, is a variant of primary progressive aphasia characterized by labored speech with agrammatism, anomia, and phonemic paraphasias, in the presence of relatively preserved word comprehension (Gorno-Tempini et al., 2004). Later in the course of the disease, patients with PNFA may develop behavioral changes, vertical gaze palsy, or

Disclosure statement

The authors have no actual or potential conflicts of interest.

Acknowledgements

Supported by grants from Ricerca Corrente, Italian Ministry of Health, and the Italian Ministry of Education, University and Research MIUR RBAP11FRE9.

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    These authors contributed equally to this work.

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