Identification of a novel polymorphism in the promoter region of the tau gene highly associated to progressive supranuclear palsy in humans

doi:10.1016/S0304-3940(99)00738-7

Neuroscience Letters

Volume 275, Issue 3, 19 November 1999, Pages 183-186

https://doi.org/10.1016/S0304-3940(99)00738-7 Get rights and content

Abstract

An intronic polymorphism and other changes in the transcribed region of the tau gene forming a haplotype have been previously described associated to progressive supranuclear palsy (PSP). These results raised the possibility that a change at or near the tau gene could be responsible for an increased risk to develop PSP. We initiated the present work in research for potential changes in the promoter region of the tau gene that could further extend the previously described haplotype. The tau promoter region was analyzed through single strand conformation polymorphism followed by direct sequencing in PSP patients (n=35), in controls (n=195) and in Alzheimer's disease (AD; n=74) patients. We have been able to identify a G to C change at position −221 of the tau gene promoter region. The CC genotype has been detected to be present with a significantly higher frequency in PSP patients (91.4%; P<0.00001; OR=11.8), but not in AD patients, as compared with controls (49.74%). Subsequently we have detected that the CC −221 tau promoter genotype is significantly associated to the tau intronic A0/A0 genotype (P<0.00001). The detected −221 tau G to C change occurs within a potential c-myb proto-oncogene element present in the promoter region. Thus, in addition to extending the previously described haplotype associated to PSP, this −221 G to C change is an interesting candidate that could provide a potential explanation for the association of the haplotype to increased risk for developing PSP.

Section snippets

Acknowledgements

This work was supported by a grant from the Fondo de Investigaciones Sanitarias (FIS96–0658) and Generalitat de Catalunya (1997 SGR-00769) to R.O.

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Assessment of common variability and expression quantitative trait loci for genome-wide associations for progressive supranuclear palsy
2014, Neurobiology of Aging
Citation Excerpt :
PSP is a primary tauopathy with widespread tau pathology mainly defined by hyperphosphorylated tau protein, neurofibrillary tangles, neuropil threads and characteristic glial tau inclusions, astrocytic tufts, and oligodendroglial-coiled bodies in the white matter (Dickson et al., 2007). By virtue of its pathology, it is not surprising that PSP risk has been consistently associated with the H1 haplotype of the tau gene (MAPT) (Baker et al., 1999; Conrad et al., 1997; Ezquerra et al., 1999) (for review, see Vandrovcova et al., 2010). While a handful of autosomal dominant PSP cases have been described (Rohrer et al., 2011; Rojo et al., 1999), the majority are sporadic, without evidence of familial clustering.
Progressive supranuclear palsy is a rare parkinsonian disorder with characteristic neurofibrillary pathology consisting of hyperphosphorylated tau protein. Common variation defining the microtubule associated protein tau gene (MAPT) H1 haplotype strongly contributes to disease risk. A recent genome-wide association study (GWAS) revealed 3 novel risk loci on chromosomes 1, 2, and 3 that primarily implicate STX6, EIF2AK3, and MOBP, respectively. Genetic associations, however, rarely lead to direct identification of the relevant functional allele. More often, they are in linkage disequilibrium with the causative polymorphism(s) that could be a coding change or affect gene expression regulatory motifs. To identify any such changes, we sequenced all coding exons of those genes directly implicated by the associations in progressive supranuclear palsy cases and analyzed regional gene expression data from control brains to identify expression quantitative trait loci within 1 Mb of the risk loci. Although we did not find any coding variants underlying the associations, GWAS-associated single-nucleotide polymorphisms at these loci are in complete linkage disequilibrium with haplotypes that completely overlap with the respective genes. Although implication of EIF2AK3 and MOBP could not be fully assessed, we show that the GWAS single-nucleotide polymorphism rs1411478 (STX6) is a strong expression quantitative trait locus with significantly lower expression of STX6 in white matter in carriers of the risk allele.
Progressive Supranuclear Palsy
2010, Blue Books of Neurology
Citation Excerpt :
The initial tau microsatellite marked a raft of variation across MAPT (the H1 haplotype) associated with PSP and occurring on 78% of control chromosomes and 94% of PSP chromosomes.52 Further work on the region indicated that there was an extensive area of linkage disequilibrium around MAPT, implicated in the PSP-MAPT or PSP-17q21 association, raising the possibility that variation in other genes and regulatory regions might play a role in the susceptibility to the development of PSP.55-58 It has been shown more recently that this area of linkage disequilibrium is due to a 900-kb inversion on 17q21, and that the rarer H2 haplotype is associated with Northern European ancestry.59-61
Progressive supranuclear palsy (PSP) is an age-dependent neurodegenerative condition, and the clinical progression of PSP has similarities to amyotrophic lateral sclerosis—with progressive loss of speech, swallowing, and ambulation in the setting of largely intact cognitive function. The presence of a vertical supranuclear gaze palsy and prominent postural instability with falls in the first year of symptoms leads to a diagnosis of clinically probable PSP, and the presence of the balance disorder with slowing of vertical saccades or an isolated supranuclear gaze palsy leads to a diagnosis of clinically possible PSP. Magnetic resonance imaging (MRI) is helpful in excluding structural lesions and in established PSP often shows midbrain and superior cerebellar peduncular atrophy, which can be used to distinguish PSP from Parkinson's disease (PD) and multiple system atrophy (MSA) associated with parkinsonism. Pathologically, PSP involves the deposition of neurofibrillary tangles (NFTs), gliosis, and cell loss in a specific distribution, particularly affecting the subthalamic nucleus, globus pallidus, substantia nigra (pars compacta and reticulata), pretectal area of the midbrain, and basis pontis. The pathological differential diagnosis of PSP includes FTDP-17T, corticobasal degeneration (CBD), and other neurodegenerative tauopathies. Cerebrospinal fluid tau analysis may become a biomarker, which might be useful in diagnosing PSP or in tracking the response to disease-modifying therapies. The molecular genetics and treatment methods of PSP are also discussed in the chapter.
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.
Genetics of progressive supranuclear palsy
2008, Handbook of Clinical Neurology
Citation Excerpt :
Further genetic and biochemical analysis of this gene and its protein would be required to ascertain any disease‐related effects. The extended MAPT H1 and H2 haplotypes were extended a further 68 kb to several SNPs in the promoter region of the gene, all of which were found to be highly associated with PSP (Ezquerra et al., 1999; de Silva et al., 2001). Further to this study, the linkage disequilibrium and association with PSP was mapped to genetic markers lying outside the limits of the MAPT gene, implicating flanking UTR and adjacent genes (Pau Pastor et al., 2002, 2004).
This chapter emphasizes that progressive supranuclear palsy (PSP) is the second most common form of degenerative parkinsonism and is characterized clinically by an akinetic-rigid syndrome, supranuclear gaze palsy, pseudobulbar signs, and cognitive decline of frontal lobe type. It is characterized neuropathologically by fibrillar aggregates of the microtubule-associated protein tau in the neurons and in the glia. Recent advances in the identification of genetic factors involved in PSP have opened up new lines of investigation in understanding the etiopathogenesis of this disorder, though it still remains unclear as to what is the primary cause of the disease. The recent cataloguing of several families with inherited PSP has demonstrated that this classically sporadic disorder does have a genetic component and has led to linkage to a novel locus, 1q31.1, in large Spanish kindred with autosomal dominant PSP. Identification of the underlying genetic lesion has the potential to greatly enhance the understanding of the molecular pathways in the pathogenesis of PSP. The chapter concludes that future studies should focus on biochemical, pathological, and clinical phenotypes in respect of genetic background.
Tau and saitohin gene expression pattern in progressive supranuclear palsy
2007, Brain Research
Citation Excerpt :
An extended haplotype in the tau gene has been associated with an increased risk of developing PSP. This suggests that genetic factors could be important in the pathogenesis of this disease (Ezquerra et al., 1999; Baker et al., 1998; Pastor et al., 2004; Pittman et al., 2004). The significance of this haplotype in PSP pathogenesis remains unclear.
Deregulation of tau mRNA splicing may contribute to causing progressive supranuclear palsy (PSP). The inclusion of exon 10 produces tau protein isoforms containing all four microtubule-binding repeats (4R). Its exclusion gives rise to isoforms with three microtubule-binding repeats (3R). Alternative splicing of exons 2 and 3 produces the 0N, 1N or 2N protein isoforms. Saitohin (STH) is a nested gene included in intron 9 of tau. It has an unknown function, but could also be involved in the pathological process associated with PSP. We used real-time PCR to investigate the level of expression of tau mRNA isoforms and STH mRNA in the frontal cortex and globus pallidus of PSP patients' brains. mRNA levels were compared with those in the brains of two controls groups: healthy controls and Alzheimer's disease patients (AD). The 4R/3R mRNA ratio was significantly higher in the globus pallidus of PSP patients than in controls. The 0N mRNA isoform levels were statistically higher in the frontal cortex and globus pallidus of AD patients and were borderline higher in the globus pallidus of PSP patients than controls. In addition, when all samples were taken into account (PSP + AD + controls), a significant correlation was found between the 4R/3R mRNA tau ratio and STH expression. This correlation was stronger in the globus pallidus than in the frontal cortex. Our results suggest that abnormalities in the alternative splicing of the tau gene are involved in the molecular mechanism related to PSP pathogenesis. Such abnormalities cause an increase in the 4R/3R ratio and may lead to an overexpression of 0N tau isoforms.
The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts
2007, Neurobiology of Disease
Citation Excerpt :
The conservation of these domains (> 75% between mouse and human) strongly implicates them as functionally important in the regulation of MAPT promoter activity. Recent work has suggested that the allelic variants of the domain containing rs242557 have altered promoter driven reporter expression (Rademakers et al., 2005) and earlier work had identified three SNPs within the conserved core promoter that were defined by the H1/H2 clades (Ezquerra et al., 1999, de Silva et al., 2001) and suggested the H1 variant of the promoter had an elevated level of transcription with respect to the H2 variant (Kwok et al., 2004). In order to assess the potential function of the two conserved domains and whether their allelic variants affected MAPT promoter transcriptional activity, we cloned the respective variants (rs7210728 (A/G) and rs252557 (A/G)) of the domains (Fig. 4A; module A and C, respectively) in context with the H1p and H2p variants of the MAPT core promoter (module B) (Andreadis et al., 1996) into a pGL4.10 luc reporter vector (Promega).
Previously we have shown that the H1c haplotype on the background of the H1 clade of haplotypes at the MAPT locus is associated with increased risk for progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Alzheimer’s disease (AD). Here we replicated the association with AD in an additional autopsy confirmed series. We show that this haplotype increases both the expression of total MAPT transcript as well as specifically increasing the proportion of 4 microtubule binding repeat containing transcripts. We discuss these findings both in terms of the problems facing the dissection of the etiologies of complex traits and the pathogenesis of the tauopathies.

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Identification of a novel polymorphism in the promoter region of the tau gene highly associated to progressive supranuclear palsy in humans

Abstract

Section snippets

Acknowledgements

Neuron

J. Biol. Chem.

Trends Neurol. Sci.

A τ promoter region without neuronal specificity

J. Neurochem.

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

Hum. Mol. Genet.

Direct genetic evidence for involvement of tau in progressive supranuclear palsy

Ann. Neurol.

Incidence of progressive supranuclear palsy and multiple system atrophy in Olmstead County, Minnesota, 1976 to 1990

Neurology

High apolipoprotein E ϵ4 allele frequency in age related memory decline

Ann. Neurol.

Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degenerative disorders linked to chromosome 17

Proc. Natl. Acad. Sci. USA

Genetic evidence for the involvement of τ in progressive supranuclear palsy

Ann. Neurol.

Overexpression of tau proteins inhibits kinesin-dependent trafficking of vesicles, mitochondria and endoplasmic reticulum: implications for Alzheimer's disease

J. Cell. Biol.

Neuronal apoptosis is associated with a decrease in tau mRNA expression

NeuroReport