The Importance of Being Connected

Lutz, Michael W.; Crenshaw, Donna G.; Saunders, Ann M.; Roses, Allen D.

doi:10.3233/jad-2010-101765

Cited by 6 publications

(6 citation statements)

References 222 publications

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“…To date, TOMM40 is the only gene identified that is thought to contribute to late onset AD-related mitochondria dysfunction [40]; however, it has been suggested that the statistically significant correlation of TOMM40 with AD risk is due to linkage disequilibrium with APOE on chromosome 19. In agreement with previous reports [41, 42], the majority of the E4 cohort in our sample (85.7%) possessed at least one ‘long’ TOMM40 variant, and the non-E4 cohort was either ‘short’ (65.8%) or ‘very long’ (34.2%).…”

Section: Discussionsupporting

confidence: 93%

Longer TOMM40 poly-T variants associated with higher FDDNP-PET medial temporal tau and amyloid binding

Siddarth¹,

Burggren

Merrill³

et al. 2018

PLoS ONE

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BackgroundThe translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium with the apolipoprotein E (APOE) gene, has been implicated in Alzheimer’s disease (AD). TOMM40 influences AD pathology through mitochondrial neurotoxicity, and the medial temporal lobe (MTL) is the most likely brain region for identifying early manifestations of AD-related morphology changes. While early reports indicated that the longer length poly-T allele of TOMM40 increases risk for AD, these findings have not been consistently replicated in further studies. We examined the effect of TOMM40 and APOE on regional brain positron emission tomography (PET) 2-(1-{6-[(2 [F18]fluoroethyl) (methyl) amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) binding values in MTL.MethodsA total of 73 non-demented older adults (42 females; mean age: 62.9(10.9) completed genotyping for both APOE and TOMM40 and received FDDNP-PET scans. For TOMM40, the lengths of the poly-T sequence were classified as short (14–20 repeats; S), long (21–29 repeats, L) or very long (>29 repeats, VL). Using general linear models, we examined medial temporal lobe FDDNP binding and cognitive functioning between TOMM40 and APOE-4 groups, with age, sex, and education as covariates.ResultsData from 30 individuals with APOE-4 and L TOMM40 poly-T length, 11 non E4 TOMM40 S/S, 14 non E4 TOMM40 S/VL and 13 non E4 TOMM40 VL/VL were analyzed. Medial temporal FDDNP binding differed significantly between TOMM40/APOE groups (F(3,62) = 3.3,p = .03). Participants with TOMM40 S/S exhibited significantly lower binding compared to TOMM40 S/VL and APOE-4 carriers. We did not find a significant relationship between TOMM40 poly-T lengths/APOE risk groups and cognitive functioning.ConclusionsThis is the first report to demonstrate a significant association between longer TOMM40 poly-T lengths and higher medial temporal plaque and tangle burden in non-demented older adults. Identifying biomarkers that are risk factors for AD will enhance our ability to identify subjects likely to benefit from novel AD treatments.

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Section: Discussionsupporting

confidence: 93%

Longer TOMM40 poly-T variants associated with higher FDDNP-PET medial temporal tau and amyloid binding

Siddarth¹,

Burggren

Merrill³

et al. 2018

PLoS ONE

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“…Linkage disequilibrium between TOMM40 and APOE genes ensures that the L poly-T repeat in the TOMM40 gene is almost always (with rare exceptions) inherited with the APOEε4 allele. However, the ε3 allele is most commonly with either a VL or an S poly-T variant, again, with rare exceptions [8,13]. In individuals homozygous for the ε3 variant, the VL variant was found to be associated with a higher risk and earlier age of onset for AD, whereas S variant carriers had a later age of onset [8].…”

Section: Introductionmentioning

confidence: 99%

“…Recent results suggest the protein encoded by the TOMM40 gene may impact the development of AD via mitochondrial function [15,16]. The protein that TOMM40 encodes, TOM40, is a mitochondrial import channel protein that facilitates the transport of amyloid-β protein precursor (APP) and amyloid-β (Aβ) transport to the mitochondria [17,18].…”

Section: Introductionmentioning

confidence: 99%

Hippocampal thinning linked to longerTOMM40poly‐T variant lengths in the absence of theAPOEε4 variant

Burggren

Mahmood

Harrison

et al. 2017

Alzheimer's & Dementia

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IntroductionThe translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium with apolipoprotein E (APOE), has received attention more recently as a promising gene in Alzheimer's disease (AD) risk. TOMM40 influences AD pathology through mitochondrial neurotoxicity, and the medial temporal lobe (MTL) is the most likely brain region for identifying early manifestations of AD‐related morphology changes.MethodsIn this study, we examined the effects of TOMM40 using high‐resolution magnetic resonance imaging in 65 healthy, older subjects with and without the APOE ε4 AD‐risk variant.ResultsExamining individual subregions within the MTL, we found a significant relationship between increasing poly‐T lengths of the TOMM40 variant and thickness of the entorhinal cortex only in subjects who did not carry the APOE ε4 allele.DiscussionOur data provide support for TOMM40 variant repeat length as an important contributor to AD‐like MTL pathology in the absence of APOE ε4.

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“…Personalized medicine providing therapies, adapted to each patient's genetic predisposition [1] [2] [3] [4] [5] , is mainly supported by the analysis of single nucleotide polymorphisms (SNPs) [1] . SNPs are single base variations and besides copy number variations the most abundant type of genetic variation found between members of one species [6] [7] [8] [9] .…”

Section: Introductionmentioning

confidence: 99%

Variants of a Thermus aquaticus DNA Polymerase with Increased Selectivity for Applications in Allele- and Methylation-Specific Amplification

et al. 2014

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The selectivity of DNA polymerases is crucial for many applications. For example, high discrimination between the extension of matched versus mismatched primer termini is desired for the detection of a single nucleotide variation at a particular locus within the genome. Here we describe the generation of thermostable mutants of the large fragment of Thermus aquaticus DNA polymerase (KlenTaq) with increased mismatch extension selectivity. In contrast to previously reported much less active KlenTaq mutants with mismatch discrimination abilities, many of the herein discovered mutants show conserved wild-type-like high activities. We demonstrate for one mutant containing the single amino acid exchange R660V the suitability for application in allele-specific amplifications directly from whole blood without prior sample purification. Also the suitability of the mutant for methylation specific amplification in the diagnostics of 5-methyl cytosines is demonstrated. Furthermore, the identified mutant supersedes other commercially available enzymes in human leukocyte antigen (HLA) analysis by sequence-specific primed polymerase chain reactions (PCRs).

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The Importance of Being Connected

Cited by 6 publications

References 222 publications

Longer TOMM40 poly-T variants associated with higher FDDNP-PET medial temporal tau and amyloid binding

Longer TOMM40 poly-T variants associated with higher FDDNP-PET medial temporal tau and amyloid binding

Hippocampal thinning linked to longerTOMM40poly‐T variant lengths in the absence of theAPOEε4 variant

Variants of a Thermus aquaticus DNA Polymerase with Increased Selectivity for Applications in Allele- and Methylation-Specific Amplification

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