Mutation screening of the tau gene in patients with early-onset Alzheimer's disease

Roks, Gerwin; Dermaut, Bart; Heutink, Peter; Julliams, Ann; Backhovens, Hubert; Broeck, Marleen Van de; Serneels, Sally; Hofman, Albert; Broeckhoven, Christine Van; Duijn, Cornelia M. van; Cruts, Marc

doi:10.1016/s0304-3940(99)00861-7

Cited by 42 publications

(25 citation statements)

References 16 publications

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“…There have been however, several genetic studies of the tau locus in AD that have provided evidence for an association (16)(17)(18) where others have not (4,(19)(20)(21). Incorporating the STH polymorphism screening in these studies could elucidate the apparent inconsistencies in these reports and help determine whether there is an association between the tau͞STH locus and AD.…”

Section: Discussionmentioning

confidence: 99%

A polymorphic gene nested within an intron of the tau gene: Implications for Alzheimer's disease

Conrad

Vianna

Freeman

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

109

124

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A previously undescribed gene, Saitohin (STH), has been discovered in the intron between exons 9 and 10 of the human tau gene. STH is an intronless gene that encodes a 128-aa protein with no clear homologs. The tissue expression of STH is similar to tau, a gene that is implicated in many neurodegenerative disorders. In humans, a single nucleotide polymorphism that results in an amino acid change (Q7R) has been identified in STH and was used in a case control study. The Q7R polymorphism appears to be over-represented in the homozygous state in late onset Alzheimer's disease subjects.

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Section: Discussionmentioning

confidence: 99%

A polymorphic gene nested within an intron of the tau gene: Implications for Alzheimer's disease

Conrad

Vianna

Freeman

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

109

124

View full text Add to dashboard Cite

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“…17 In the proband mutations in PSEN1, PSEN2 and APP were also excluded by RT-PCR analysis and genomic sequencing. 6 Also, direct sequencing of the coding region of PRNP (Dermaut et al, unpublished data), and of exons 9-13 coding for the microtubule binding domains of MAPT 18 did not reveal mutations. The apolipoprotein E (APOE) genotype of all available family members was determined using PCR amplification and digestion with HhaI, 20 and indicated that all had the APOE ⑀3⑀3 genotype 17 (and this paper).…”

Section: Subjectsmentioning

confidence: 95%

“…6,18 In a recent follow-up study it was shown that the phenotype in family 1083 most closely resembled that of FTD, and a neuropathological study of one patient revealed taunegative, ubiquitin-positive neuronal inclusions. Although we observed strong linkage to a 4.8-cM region at 17q21 containing MAPT, we did not detect mutations in MAPT despite extensive screening, suggesting that the tauopathy negative FTD in family 1083 might be caused by a variation in another distinctive gene within 17q21.…”

Section: Introductionmentioning

confidence: 99%

Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval

Rademakers¹,

Cruts²,

Dermaut³

et al. 2002

Mol Psychiatry

102

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We report the results of a genome-wide search in a four-generation pedigree with autosomal dominant early-onset dementia (mean onset age: 64.9 years, range 53-79 years). In this family we previously excluded the known Alzheimer's disease genes based on linkage analysis and mutation screening of the amyloid precursor protein gene (exons 16 and 17) and the presenilin 1 and 2 genes. In addition we excluded mutations in the prion protein gene and exons 9-13 of the microtubule associated protein tau (MAPT) gene. We obtained conclusive linkage with chromosome 17q21 markers with a maximum multi-point LOD score of 5.51 at D17S951 and identified a candidate region of 4.8 cM between D17S1787 and D17S958 containing MAPT. Recent clinical and neuropathological follow-up of the family showed that the phenotype most closely resembled frontotemporal dementia (FTD) characterized by dense ubiquitin-positive neuronal inclusions that were tau negative. Extensive mutation analysis of MAPT identified 38 sequence variations in exons, introns, untranslated regions and the 5Ј regulatory sequence, however none was comprised within the disease haplotype. Although our findings do not entirely exclude a mutation in a yet unanalyzed region of MAPT, the apparent absence of MAPT mutations combined with the lack of tau pathology is highly suggestive for another defective gene at 17q21 responsible for FTD in this family.

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“…13,16 The H1c variant of this haplotype is reported to be the predominant cause of the H1 association with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) 17,20,21 and more recently has been associated with AD. 16 Prior studies of MAPT associations with AD had produced inconclusive findings; 14,15,[22][23][24][25] however, the study of Myers et al 16 was the first study to assess the impact of this H1 diversity. It was previously clear that tau was intimately involved in AD pathology, owing to neurofibrillary tangles, along with senile plaques, being the characteristic pathological hallmarks of the disease.…”

Section: Introductionmentioning

confidence: 99%

Fine mapping of the MAPT locus using quantitative trait analysis identifies possible causal variants in Alzheimer's disease

et al. 2006

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In addition to senile plaques, neurofibrillary tangles are characteristic of Alzheimer's disease (AD) pathology, suggesting a clear involvement of the microtubule-associated protein tau (MAPT) in AD. Recent findings, suggesting that the H1c haplotype is associated with increased risk, now also implicate MAPT genetically. In this study, we aim to clarify this association by a fine mapping approach using both a traditional phenotypic association analysis and a quantitative trait (QT) analysis using cerebrospinal fluid (CSF) tau protein levels in the German population. Here, we report that both methodologies identify that the H1c haplotype may play important role in AD (AD risk, P = 0.007, uncorrected; CSF tau levels, P = 0.027, uncorrected). Further, the use of a sliding window approach in the QT analysis allowed for the narrowing down of the region where a probable causal variant may be located. The data suggest that this may lie at or within close proximity to the rs242557 single nucleotide polymorphism as association with CSF tau levels seems to be primarily driven by rs242557 in a gene dosagedependent manner (trend model: P = 0.002, uncorrected). These findings provide functional evidence to support the genetic association of MAPT with AD.

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Mutation screening of the tau gene in patients with early-onset Alzheimer's disease

Cited by 42 publications

References 16 publications

A polymorphic gene nested within an intron of the tau gene: Implications for Alzheimer's disease

A polymorphic gene nested within an intron of the tau gene: Implications for Alzheimer's disease

Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval

Fine mapping of the MAPT locus using quantitative trait analysis identifies possible causal variants in Alzheimer's disease

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