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Role for the microtubule-associated protein tau variant p.A152T in risk of ?-synucleinopathies.

ABSTRACT: To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies.In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls.The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63-2.98, p = 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62-20.51, p = 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04-12.17, p = 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85-25.72, p = 0.08) but this was not statistically significant and therefore should be interpreted with caution.Overall, our findings suggest that MAPT p.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies.

SUBMITTER: Labbe C

PROVIDER: S-EPMC4653108 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Role for the microtubule-associated protein tau variant p.A152T in risk of α-synucleinopathies.

Labbé Catherine C Ogaki Kotaro K Lorenzo-Betancor Oswaldo O Soto-Ortolaza Alexandra I AI Walton Ronald L RL Rayaprolu Sruti S Fujioka Shinsuke S Murray Melissa E ME Heckman Michael G MG Puschmann Andreas A McCarthy Allan A Lynch Timothy T Siuda Joanna J Opala Grzegorz G Rudzinska Monika M Krygowska-Wajs Anna A Barcikowska Maria M Czyzewski Krzysztof K Sanotsky Yanosh Y Rektorová Irena I McLean Pamela J PJ Rademakers Rosa R Ertekin-Taner Nilüfer N Hassan Anhar A Ahlskog J Eric JE Boeve Bradley F BF Petersen Ronald C RC Maraganore Demetrius M DM Adler Charles H CH Ferman Tanis J TJ Parisi Joseph E JE Graff-Radford Neill R NR Uitti Ryan J RJ Wszolek Zbigniew K ZK Dickson Dennis W DW Ross Owen A OA

Neurology 20150902 19

<h4>Objective</h4>To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies.<h4>Methods</h4>In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy con ...[more]

PMID: 26333800

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Project description:BackgroundThe microtubule associated protein Tau (MAPT) promotes assembly and interaction of microtubules with the cytoskeleton, impinging on axonal transport and synaptic plasticity. Its neuronal expression and intrinsic disorder implicate it in some 30 tauopathies such as Alzheimer's disease and frontotemporal dementia. These pathophysiological studies have yet to be complemented by computational analyses of its molecular evolution and structural models of all its functional domains to explain the molecular basis for its conservation profile, its site-specific interactions and the propensity to conformational disorder and aggregate formation.ResultsWe systematically annotated public sequence data to reconstruct unspliced MAPT, MAP2 and MAP4 transcripts spanning all represented genomes. Bayesian and maximum likelihood phylogenetic analyses, genetic linkage maps and domain architectures distinguished a nonvertebrate outgroup from the emergence of MAP4 and its subsequent ancestral duplication to MAP2 and MAPT. These events were coupled to other linked genes such as KANSL1L and KANSL and may thus be consequent to large-scale chromosomal duplications originating in the extant vertebrate genomes of hagfish and lamprey. Profile hidden Markov models (pHMMs), clustered subalignments and 3D structural predictions defined potential interaction motifs and specificity determining sites to reveal distinct signatures between the four homologous microtubule binding domains and independent divergence of the amino terminus.ConclusionThese analyses clarified ambiguities of MAPT nomenclature, defined the order, timing and pattern of its molecular evolution and identified key residues and motifs relevant to its protein interaction properties and pathogenic role. Additional unexpected findings included the expansion of cysteine-containing, microtubule binding domains of MAPT in cold adapted Antarctic icefish and the emergence of a novel multiexonic saitohin (STH) gene from repetitive elements in MAPT intron 11 of certain primate genomes.

Dataset Information

Role for the microtubule-associated protein tau variant p.A152T in risk of ?-synucleinopathies.

Publications

Role for the microtubule-associated protein tau variant p.A152T in risk of α-synucleinopathies.

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