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

Rossi, Giacomina; Bastone, Antonio; Piccoli, Elena; Morbin, Michela; Mazzoleni, Giulia; Fugnanesi, Valeria; Beeg, Marten; Favero, Elena Del; Cantù, Laura; Motta, S.; Salsano, Ettore; Pareyson, Davide; Erbetta, Alessandra; Elia, Antonio E.; Sorbo, Francesca Del; Silani, Vincenzo; Morelli, Claudia; Salmona, Mario; Tagliavini, Fabrizio

doi:10.1016/j.neurobiolaging.2013.08.004

Cited by 42 publications

(42 citation statements)

References 56 publications

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“…Until recently, mutation screens in PCA have been limited to case reports which identified PSEN1 I211M (Sitek et al, 2013), PSEN1 G223R (Saint-Aubert et al, 2013), PSEN2 M239I (Tremolizzo et al, 2014), MAPT V363I (Rossi et al, 2014), GRN R110X (Caroppo et al, 2015), in addition to a family with PCA phenotype in which a 120 base pair octapeptide repeat insertion mutation was identified within PRNP (Depaz et al, 2012). A mutation screen of known dementia genes in a cohort of 227 early-onset probable AD subjects revealed PSEN1 P218L and PSEN1 I238M mutations in two subjects with memory and vision loss, although this was not a specific screen for PCA (Wojtas et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…To date, there are six case reports of PCA patients with mutations in known dementia genes (Caroppo et al, 2015; Depaz et al, 2012; Rossi et al, 2014; Saint-Aubert et al, 2013; Sitek et al, 2013; Tremolizzo et al, 2014). Of these six variants, four ( PSEN1 G223R, PSEN2 M239I, MAPT V363I, and GRN R110X) are listed in the AD&FTDMUTDB, as “pathogenic”, but only PSEN2 M239I is included on the NeuroX array.…”

Section: Methodsmentioning

confidence: 99%

“…Further, given that the onset age for PCA is generally younger, thus often prompting clinical genetic screens, discovery of the full pathogenic mutation spectrum that can lead to PCA can aid the clinician in the choice of genetic tests. To date, there are only case reports of PCA subjects with missense variants in genes previously implicated in early-onset AD (EOAD) (Saint-Aubert et al, 2013; Sitek et al, 2013; Tremolizzo et al, 2014), frontotemporal dementia (FTD) (Caroppo et al, 2015; Rossi et al, 2014), and Creutzfeldt-Jakob disease (CJD) (Depaz et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

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Evaluating pathogenic dementia variants in posterior cortical atrophy

Carrasquillo

Barber

Lincoln

et al. 2016

Neurobiology of Aging

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Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to “posterior Alzheimer’s disease (AD)” pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n=67) or posterior AD neuropathology (n=57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array. Frequencies in PCA of the variants annotated as pathogenic or potentially pathogenic were compared against ~4,300 European-American population controls from the NHLBI Exome Sequencing Project (ESP). We identified two rare variants not previously reported in PCA, TREM2 Arg47His and PSEN2 Ser130Leu. No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes. In this first systematic variant screen of a PCA cohort, we report two rare mutations in TREM2 and PSEN2, validate our previously reported APOE ε4 association, and demonstrate the utility of NeuroX.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluating pathogenic dementia variants in posterior cortical atrophy

Carrasquillo

Barber

Lincoln

et al. 2016

Neurobiology of Aging

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“…35 After tau is encoded, six isoforms can form by various splicing of exons 2, 3, or 10 on the microtubule-binding domain of pre-mRNA. 36 The exon 10 splice variant, hTau40, is the most important in neurodegenerative disease development, and is found specifically in the central nervous system.…”

Section: Tau Isoforms and Tau Mutationsmentioning

confidence: 99%

Linking Traumatic Brain Injury to Chronic Traumatic Encephalopathy: Identification of Potential Mechanisms Leading to Neurofibrillary Tangle Development

Lucke‐Wold

Turner²,

Logsdon³

et al. 2014

Journal of Neurotrauma

112

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Significant attention has recently been drawn to the potential link between head trauma and the development of neurodegenerative disease, namely chronic traumatic encephalopathy (CTE). The acute neurotrauma associated with sportsrelated concussions in athletes and blast-induced traumatic brain injury in soldiers elevates the risk for future development of chronic neurodegenerative diseases such as CTE. CTE is a progressive disease distinguished by characteristic tau neurofibrillary tangles (NFTs) and, occasionally, transactive response DNA binding protein 43 (TDP43) oligomers, both of which have a predilection for perivascular and subcortical areas near reactive astrocytes and microglia. The disease is currently only diagnosed postmortem by neuropathological identification of NFTs. A recent workshop sponsored by National Institute of Neurological Disorders and Stroke emphasized the need for premortem diagnosis, to better understand disease pathophysiology and to develop targeted treatments. In order to accomplish this objective, it is necessary to discover the mechanistic link between acute neurotrauma and the development of chronic neurodegenerative and neuropsychiatric disorders such as CTE. In this review, we briefly summarize what is currently known about CTE development and pathophysiology, and subsequently discuss injury-induced pathways that warrant further investigation. Understanding the mechanistic link between acute brain injury and chronic neurodegeneration will facilitate the development of appropriate diagnostic and therapeutic options for CTE and other related disorders.

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“…4 Finally, a PCA patient carrying the V363I mutation in the microtubule-associated protein tau gene has been reported very recently. 5 Herein, we describe the first PCA case due to a rare mutation within the presenilin 2 (PSEN2) gene.…”

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confidence: 99%