A New Mutation of the τ Gene, G303V, in Early-Onset Familial Progressive Supranuclear Palsy

Abstract

Background: Progressive supranuclear palsy (PSP) is a clinicopathological syndrome related to deposits and in linkage disequilibrium with polymorphisms. Some rare familial PSP cases have been related to gene mutations. Objective: To present the clinical, pathological, and molecular data of one family with early-onset autosomal dominant PSP. Design: We performed clinical examinations, quantitative neurological tests, positron emission tomographic scans with fluorodopa F 18 and raclopride C 11, analysis of mutations, neuropathological examinations, and protein analyses on brain specimens. Results: Three family members had PSP confirmed by pathological features in the proband. A novel mutation of , G303V, was found in the proband and other family members. Isoforms with 4 microtubule-binding repeats were overexpressed in the proband brain. Conclusions: The G303V mutation of is associated with autosomal dominant PSP. Expression of 4 microtubulebinding repeat isoforms is increased in the proband.

Three sib-pairs of autopsy-confirmed progressive supranuclear palsy

“…Interestingly, more than half of the patients carrying the tau p.G303V substitution had falls within one year of symptomatic onset [11]. For patients with the tau p.R5L, p.S285R, and p.G303S substitutions, early falls also were a common feature [6, 7, 9]. In our cases with MAPT mutation, both affected siblings had a young age of onset.…”

Three sib-pairs of autopsy-confirmed progressive supranuclear palsy

“…Interestingly, more than half of the patients carrying the tau p.G303V substitution had falls within one year of symptomatic onset [11]. For patients with the tau p.R5L, p.S285R, and p.G303S substitutions, early falls also were a common feature [6, 7, 9]. In our cases with MAPT mutation, both affected siblings had a young age of onset.…”

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

“…Staining of Fkbp5 -/-mice revealed a significant reduction in tau levels throughout the brain (Figure 1, A-C). Similarly, Western blot analyses of brain homogenates showed similar reductions in several tau epitopes, including a significant reduction in total tau (as assessed with the Tau 12 [amino acids [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Tau expression is decreased in the Fkbp5 -/-mice and associates with FKBP51 in the AD brain. Representative images of brain tissue from (A) wild-type and (B) Fkbp5 -/-mice stained for pT231 tau and corresponding sections without primary (no primary).…”

VEGF Haplotypes are Associated with Increased Risk to Progressive Supranuclear Palsy and Corticobasal Syndrome

“…It has been suggested that genetic background plays a crucial role in PSP and CBS pathogenesis, and in some cases autosomal dominant pattern of inheritance may be recognized [5,6]. The high incidence of positive family history recently demonstrated in these patients further supports the genetic weight in these atypical extrapyramidal syndromes [7].…”

Three sib-pairs of autopsy-confirmed progressive supranuclear palsy

“…Interestingly, more than half of the patients carrying the tau p.G303V substitution had falls within one year of symptomatic onset [11]. For patients with the tau p.R5L, p.S285R, and p.G303S substitutions, early falls also were a common feature [6, 7, 9]. In our cases with MAPT mutation, both affected siblings had a young age of onset.…”

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

“…Staining of Fkbp5 -/-mice revealed a significant reduction in tau levels throughout the brain (Figure 1, A-C). Similarly, Western blot analyses of brain homogenates showed similar reductions in several tau epitopes, including a significant reduction in total tau (as assessed with the Tau 12 [amino acids [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Tau expression is decreased in the Fkbp5 -/-mice and associates with FKBP51 in the AD brain. Representative images of brain tissue from (A) wild-type and (B) Fkbp5 -/-mice stained for pT231 tau and corresponding sections without primary (no primary).…”

VEGF Haplotypes are Associated with Increased Risk to Progressive Supranuclear Palsy and Corticobasal Syndrome

“…It has been suggested that genetic background plays a crucial role in PSP and CBS pathogenesis, and in some cases autosomal dominant pattern of inheritance may be recognized [5,6]. The high incidence of positive family history recently demonstrated in these patients further supports the genetic weight in these atypical extrapyramidal syndromes [7].…”

Three sib-pairs of autopsy-confirmed progressive supranuclear palsy

“…Interestingly, more than half of the patients carrying the tau p.G303V substitution had falls within one year of symptomatic onset [11]. For patients with the tau p.R5L, p.S285R, and p.G303S substitutions, early falls also were a common feature [6, 7, 9]. In our cases with MAPT mutation, both affected siblings had a young age of onset.…”

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

“…Staining of Fkbp5 -/-mice revealed a significant reduction in tau levels throughout the brain (Figure 1, A-C). Similarly, Western blot analyses of brain homogenates showed similar reductions in several tau epitopes, including a significant reduction in total tau (as assessed with the Tau 12 [amino acids [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Tau expression is decreased in the Fkbp5 -/-mice and associates with FKBP51 in the AD brain. Representative images of brain tissue from (A) wild-type and (B) Fkbp5 -/-mice stained for pT231 tau and corresponding sections without primary (no primary).…”

VEGF Haplotypes are Associated with Increased Risk to Progressive Supranuclear Palsy and Corticobasal Syndrome

“…It has been suggested that genetic background plays a crucial role in PSP and CBS pathogenesis, and in some cases autosomal dominant pattern of inheritance may be recognized [5,6]. The high incidence of positive family history recently demonstrated in these patients further supports the genetic weight in these atypical extrapyramidal syndromes [7].…”