Novel P397S <i>MAPT</i> variant associated with late onset and slow progressive frontotemporal dementia

Borrego‐Écija, Sergi; Antonell, Anna; Puig-Butillé, Joan Antón; Pericot, Inmaculada; Prat-Bravo, Carme; Abellán-Vidal, M.T.; Mallada, Javier; Olives, Jaume; Falgàs, Neus; Oliva, Rafael; Lladó, Albert; Sánchez‐Valle, Raquel

doi:10.1002/acn3.50844

Cited by 6 publications

(6 citation statements)

References 30 publications

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“…The MAPT c.1189C>T (p.Pro397Ser) variant was identified in three independent families from the same geographic region that shared IDB segment of 2.89 cM overlapping the locus (Additional file 1: Figures S23 and S24). This variant had been previously reported in five apparently unrelated Spanish families [42], and like the Spanish counterpart, the Colombian MAPT c.1189C>T (p.Pro397Ser) carriers had variable expressivity of the illness (Additional file 9: Table S7 and Additional file 10: Table S8). To elucidate whether the Colombian MAPT c.1189C>T (p.Pro397Ser) carriers were IBD with the Spanish families, we used exome sequencing data from a Spanish patient to search for similarities in the variant carrying haplotype.…”

Section: Variants In Ftld-mnd Associated Genessupporting

confidence: 52%

“…To compare the TANGL genomes to previously identified carriers of MAPT c.1189C>T (p.Pro397Ser) from Spain, we obtained exome sequencing data from an individual previously sequenced by the Alzheimer's disease and other cognitive disorders unit at Hospital Clínic de Barcelona. The exome from the Spanish c.1189C>T (p.Pro397Ser) carrier [42] was processed from fastq to VCF using a standard clinical alignment pipeline from the HudsonAlpha Institute for Biotechnology Clinical Services Laboratory that uses Sentieon version 201808.07 (a computational wrapper for common tools such as bwa), including alignment with Sentieon-BWA (version 201808.07; identical to bwa mem 0.7.15-r1140) and variant calling with Illumina Strelka2 (version 2.9.10) [43]. The use of this sample was approved by the IRB from the "Hospital Clinic de Barcelona.…”

Section: Genome Sequencingmentioning

confidence: 99%

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A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

et al. 2022

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Background The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. Methods We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer’s disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. Results We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. Conclusions Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

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Section: Variants In Ftld-mnd Associated Genessupporting

confidence: 52%

Section: Genome Sequencingmentioning

confidence: 99%

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

et al. 2022

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“…AD-like presentation and slow progression have already been associated with other MAPT mutations [13,14] and in some cases, a mixed 3R and 4R tau pathology with neurofibrillary tangles similar to AD was found. This is also demonstrated for the G335A MAPT mutation, contiguous to the codon 336 mutation of our patients, characterized by a very early onset and mixed 3R and 4R tau, without Pick bodies [15].…”

Section: Discussionmentioning

confidence: 89%

MAPT Q336H mutation: Intrafamilial phenotypic heterogeneity in a new Italian family

Villa

Rossi

Bizzozero

et al. 2022

Euro J of Neurology

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Background and purpose: Q336H is a rare MAPT mutation, previously found in a single patient with behavioral variant frontotemporal dementia and tau pathology (Pick bodies).Here, we describe the clinical characteristics of two members of a new family carrying the Q336H MAPT mutation.Methods: Clinical, genetic, and neuroradiological assessment and follow-up of the proband were made.Results: At age 37 years, the proband developed naming and object recognition impairment, due to a lack of knowledge. After 3 years, he developed behavioral disorders.Magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography showed the involvement of the left temporal pole. A diagnosis of semantic variant primary progressive aphasia (svPPA) was made. At follow-up after 6 and 12 months, a rapid worsening of cognitive deficits occurred. His parent presented, at age 65 years, slowly progressive memory deficits without behavioral impairment, and, on MRI, evidence of mesial temporal atrophy, consistent with a clinical diagnosis of Alzheimer disease (AD).Conclusions: This is the second family carrying the MAPT Q336H mutation reported so far. We showed that svPPA and AD-like phenotype can be associated with this mutation. A wide clinical variability exists at the intrafamilial level for Q336H MAPT mutation, pointing to genetic and/or environmental influencing factors on disease expression. We also confirmed that svPPA can be associated with MAPT mutations, suggesting that this gene should be analyzed also in patients with svPPA, especially with early onset. In addition, an AD-like phenotype may be associated with this mutation, suggesting its different effects on protein misfolding and aggregation.

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“…For the D348G mutation, ALS seems to be caused by tau accumulation due to evasion of proteasomal degradation [ 119 , 120 ]. The S352L, S356T, P364S, G366R, P397S, R406W and T427M mutations were found in FTLD, FTD or PD patients [ 121 , 122 , 123 , 124 , 125 , 126 ]. Notably, the P364S tau showed a special propensity for aggregation, even higher than that of P301L tau.…”

Section: Tau Protein Metabolismmentioning

confidence: 99%

“…Moreover, P364 (in R4) corresponds to the residue P301 in R2 and to P322 in R3, whose mutations were strongly associated with different tauopathies [ 123 ]. It is also worth noting that more C-terminal mutations (P397S, R406W and T427M) were associated with later age of onset and/or longer disease duration, which suggests that the C-terminal part of the protein is less critical for tau-mediated pathology [ 124 , 125 , 126 ].…”

Section: Tau Protein Metabolismmentioning

confidence: 99%

Tau mRNA Metabolism in Neurodegenerative Diseases: A Tangle Journey

et al. 2022

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Tau proteins are known to be mainly involved in regulation of microtubule dynamics. Besides this function, which is critical for axonal transport and signal transduction, tau proteins also have other roles in neurons. Moreover, tau proteins are turned into aggregates and consequently trigger many neurodegenerative diseases termed tauopathies, of which Alzheimer’s disease (AD) is the figurehead. Such pathological aggregation processes are critical for the onset of these diseases. Among the various causes of tau protein pathogenicity, abnormal tau mRNA metabolism, expression and dysregulation of tau post-translational modifications are critical steps. Moreover, the relevance of tau function to general mRNA metabolism has been highlighted recently in tauopathies. In this review, we mainly focus on how mRNA metabolism impacts the onset and development of tauopathies. Thus, we intend to portray how mRNA metabolism of, or mediated by, tau is associated with neurodegenerative diseases.

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Novel P397S MAPT variant associated with late onset and slow progressive frontotemporal dementia

Cited by 6 publications

References 30 publications

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

MAPT Q336H mutation: Intrafamilial phenotypic heterogeneity in a new Italian family

Tau mRNA Metabolism in Neurodegenerative Diseases: A Tangle Journey

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