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

doi:10.1016/S0304-3940(99)00861-7

Neuroscience Letters

Volume 277, Issue 2, 24 December 1999, Pages 137-139

https://doi.org/10.1016/S0304-3940(99)00861-7 Get rights and content

Abstract

Hyperphosphorylated microtubule associated protein tau, present in neurofibrillary tangles, is a prominent pathological feature of Alzheimer's disease (AD). The gene encoding tau (MAPT) was recently found mutated in frontotemporal dementia (FTD) and other tauopathies. We studied MAPT as a candidate gene in the etiology of AD. The study population consisted of 101 early-onset AD patients and 117 controls. Mutation analysis did not detect causal mutations in exons 9 to 13 encoding the microtubule-binding domains involved in FTD, however, two novel polymorphisms were detected in exon 9. Using the Ala169 polymorphism in exon 9 and a previously reported (CA)_n-repeat polymorphism in intron 9, an association study was performed. No association with early-onset AD was detected. Together, our data indicate that MAPT does not play a role in early-onset AD.

Section snippets

Acknowledgements

This study was made possible by financial support from the Fund for Scientific Research Flanders (Belgium; FWO-F), DWTC Interuniversity Attractionpoles (IUAP), the International Alzheimer's Research Foundation (IARF) and grants of the Netherlands Organization for Scientific Research (NWO), the Netherlands Institute for Health Sciences (NIHES), the Hersenstichting Nederland (HsN). Marc Cruts is a postdoctoral fellow and Bart Dermaut a Ph.D. fellow of the FWO-F. We thank Drs. Wim Schulte, Teun

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The +347 C promoter allele up-regulates MAPT expression and is associated with Alzheimer's disease among the Chinese Han
2009, Neuroscience Letters
The microtubule-associated protein tau has been known to be associated with the pathogenesis of Alzheimer's disease (AD). We identified a novel single nucleotide polymorphism (SNP) in the promoter region of the microtubule-associated protein tau gene (MAPT) in Chinese Han population: 347G/C. The samples we analyzed were all identified as H1/H1 genotype; the 347C allele was over-represented in 252 sporadic AD patients (84.3%, P = 0.006) when compared with 197 controls (75.1%). The transcriptional activity of SNP in promoter was further investigated using a luciferase reporter assay in two human cell lines, SH-SY5Y and Hela. We demonstrated that the promoter transcriptional activity of the 347 C/C genotype was significantly higher than that of the 347 G/G genotype (SH-SY5Y, P = 0.0321; Hela, P = 0.0016). Our data suggest that the 347C polymorphism in the promoter of MAPT gene, which is associated with an up-regulation of the gene expression, is a susceptibility factor in sporadic AD.
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2005, American Journal of Human Genetics
We obtained conclusive linkage of Alzheimer disease (AD) with a candidate region of 19.7 cM at 7q36 in an extended multiplex family, family 1270, ascertained in a population-based study of early-onset AD in the northern Netherlands. Single-nucleotide polymorphism and haplotype association analyses of a Dutch patient-control sample further supported the linkage at 7q36. In addition, we identified a shared haplotype at 7q36 between family 1270 and three of six multiplex AD-affected families from the same geographical region, which is indicative of a founder effect and defines a priority region of 9.3 cM. Mutation analysis of coding exons of 29 candidate genes identified one linked synonymous mutation, g.38030G→C in exon 10, that affected codon 626 of the PAX transactivation domain interacting protein gene (PAXIP1). It remains to be determined whether PAXIP1 has a functional role in the expression of AD in family 1270 or whether another mutation at this locus explains the observed linkage and sharing. Together, our linkage data from the informative family 1270 and the association data in the population-based early-onset AD patient-control sample strongly support the identification of a novel AD locus at 7q36 and re-emphasize the genetic heterogeneity of AD.
Tau protein as a differential biomarker of tauopathies
2005, Biochimica et Biophysica Acta - Molecular Basis of Disease
Microtubule-associated Tau proteins are the basic component of intraneuronal and glial inclusions observed in many neurological disorders, the so-called tauopathies. Many etiological factors, phosphorylation, splicing, and mutations, relate Tau proteins to neurodegeneration. Molecular analysis has revealed that hyperphosphorylation and abnormal phosphorylation might be one of the important events in the process leading to tau intracellular aggregation. Specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution, could characterize five main classes of tauopathies. A direct correlation has been established between the regional brain distribution of tau pathology and clinical symptoms; for instance progressive involvement of neocortical areas is well correlated to the severity of dementia in Alzheimer's disease, overall suggesting that pathological tau proteins are reliable marker of the neurodegenerative process. Recent discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 has reinforced the predominant role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies. Overall, a better knowledge of the etiological factors responsible for the aggregation of tau proteins in brain diseases is essential for development of future differential diagnosis and therapeutic strategies. They would hopefully find their application against Alzheimer's disease but also in all neurological disorders for which a dysfunction of Tau biology has been identified.
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Filamentous tau deposits are a defining feature of a number of human neurodegenerative diseases. Apes and monkeys have been reported to be differentially susceptible to developing tau pathology. Despite this, only little is known about the organisation and sequence of Tau from nonhuman primates. Here we have sequenced Tau exons 1–13, including flanking intronic regions, and the region in intron 9 that contains Saitohin in chimpanzees, gorillas, and gibbons. Partial sequences were obtained for cynomolgus macaque and green monkey. Chimpanzee brain tau was 100% identical to human tau. Identities were 99.5% for gorilla tau and 99.0% for gibbon tau. Chimpanzee DNA was polymorphic for a repeat in intron 9, which was present in human and gorilla tau, and for the nucleotide at position +29 of the intron that follows exon 10. As was the case of the other nonhuman primates examined, chimpanzee DNA was homozygous for nucleotides used to define the H2 haplotype in human Tau. These differences between human and chimpanzee Tau may contribute to the apparent resistance of chimpanzee brain to developing tau pathology. Sequencing of Saitohin revealed an intact open reading frame in chimpanzee and gorilla, but not in gibbon or macaque.
Microtubule-associated protein tau gene: A risk factor in human neurodegenerative diseases
2004, Neurobiology of Disease
Tau is a microtubule-associated protein mainly expressed in neurons of central nervous system, which is crucial in the maintenance of these cells. It has a central role in the polymerization and stabilization of microtubules and in the traffic of organelles along axons and dendrites. Aggregates of hyperphosphorylated forms of tau protein participate in the formation of neurofibrillary tangles, which characterize numerous neurodegenerative disorders named tauopathies. The analysis of tau gene and the study of familial cases of tauopathies have led to the discovery of tau gene mutations that cause inherited dementia designated as Frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17). However, these familial cases remain rare compared to the sporadic tauopathies, the later involving both genetic and environmental etiologic factors. As tau pathology represents a primary pathogenic event in various neurodegenerative diseases, the hypothesis that tau genotype could influence the development of these diseases was tested by several groups. This review summarizes advances in the molecular genetics of the tau gene, as well as recent studies addressing the disease incidence of novel tau polymorphisms in different neurodegenerative diseases. Hopefully, the identification of several genetic defects of the tau gene will be helpful in improving our understanding of the role of tau protein in the pathogenesis of various neurodegenerative diseases.

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View full text

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

Abstract

Section snippets

Acknowledgements

Neurosci. Lett.

Trends Neurosci.

Am. J. Hum. Genet.

Association of an extended haplotype in the tau gene with progressive supranuclear palsy

Hum. Mol. Genet.

Neuropathological stageing of Alzheimer-related changes

Acta Neuropathol.

Genetic evidence for the involvement of tau in progressive supranuclear palsy

Ann. Neurol.

Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements

Proc. Natl. Acad. Sci. USA

Progressive supranuclear gaze palsy is in linkage disequilibrium with the tau and not the alpha-synuclein gene

Neurology

Determinants of disease and disability in the elderly: the Rotterdam elderly study

Eur. J. Epidemiol.