Regular articleDifferent mutations at V363 MAPT codon are associated with atypical clinical phenotypes and show unusual structural and functional features
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.
References (57)
- et al.
Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS
Neuron
(2013) - et al.
Semantic dementia associated with mutation V363I in the tau gene
J. Neurol. Sci.
(2010) - et al.
Heterologous stacking of prion protein peptides reveals structural details of fibrils and facilitates complete inhibition of fibril growth
J. Biol. Chem.
(2009) - et al.
Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
Neuron
(2011) - et al.
Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP
Neurobiol. Aging
(2010) - et al.
Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly
FEBS Lett.
(1998) - et al.
Removal of pattern-breaking sequences in microtubule binding repeats produces instantaneous tau aggregation and toxicity
J. Biol. Chem.
(2006) - et al.
Increased levels of granular tau oligomers: an early sign of brain aging and Alzheimer's disease
Neurosci. Res.
(2006) - et al.
Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study
Lancet Neurol.
(2012) A constrained regularization method for inverting data represented by linear algebraic or integral equations
Comp. Phys. Commun.
(1982)
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
Neuron
New mutations in MAPT gene causing frontotemporal lobar degeneration: biochemical and structural characterization
Neurobiol. Aging
Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein
Am. J. Pathol.
Glycogen synthase kinase-3beta phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice
J. Biol. Chem.
MAPT V363I variation in a sporadic case of frontotemporal dementia: variable penetrant mutation or rare polymorphism?
Alzheimer Dis. Assoc. Disord.
Association of an extended haplotype in the tau gene with progressive supranuclear palsy
Hum. Mol. Genet.
Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17
Nature
Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias
Biochemistry
Posterior cortical atrophy
Arch. Neurol.
Accumulation of pathological tau species and memory loss in a conditional model of tauopathy
J. Neurosci.
Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases
Hum. Mol. Genet.
Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21
Nature
Locus-specific mutation databases for neurodegenerative brain diseases
Hum. Mutat.
Long-standing prion dementia manifesting as posterior cortical atrophy
Alzheimer Dis. Assoc. Disord.
Microtubule polymerization dynamics
Annu. Rev. Cell. Dev. Biol.
Parkinsonism and frontotemporal dementia: The clinical overlap
J. Mol. Neurosci.
Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans
Nature
Pathogenesis of the tauopathies
J. Mol. Neurosci.
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These authors contributed equally to this work.