ClinVar Genomic variation as it relates to human health

In a large Dutch kindred with frontotemporal dementia (600274) reported by Heutink et al. (1997), Hutton et al. (1998) found a pro301-to-leu mutation (P301L) in exon 10 of the MAPT gene. The same mutation was found in a small kindred from the United States. This substitution occurred in a highly conserved region of the MAPT sequence, where a proline residue was found in all mammalian species from which tau had been cloned to that time. The P301L mutation would affect only the 4-repeat tau isoforms because exon 10 is spliced out of mRNA that encodes the 3-repeat isoforms. Analysis of tau aggregates in affected brains from the U.S. kindred revealed that these consist mainly of 4-repeat isoforms, consistent with the mutation affecting exon 10. In a note added in proof, Poorkaj et al. (1998) described finding a C-to-T transition at nucleotide 728 of the MAPT gene in a newly ascertained family with FTDP17. The mutation resulted in a PRO243LEU mutation. This is the same mutation as that reported by Hutton et al. (1998), who used a different numbering system for the nucleotides and codons. At the time the paper of Poorkaj et al. (1998) was submitted, the longest amino acid form of tau in the database did not include all of the alternatively spliced exons (Poorkaj, 1998). MAPT transcripts that contain this exon 10 mutation encode tau isoforms with 4 microtubule (MT)-binding repeats (4Rtau) as opposed to tau isoforms with 3 MT-binding repeats (3Rtau). Clark et al. (1998) found that brains of patients with the P301L missense mutation contained aggregates of insoluble 4Rtau in filamentous inclusions, which may lead to neurodegeneration. Using purified recombinant proteins, Alonso et al. (2004) showed that several FTDP17-associated tau mutations, including P301L, made tau a more favorable substrate for abnormal hyperphosphorylation compared with wildtype tau. Both the phosphorylation kinetics, due to induced conformational changes, and the phosphorylation stoichiometry, due to increased phosphorylation of more than a single site, were more favorable in the mutant proteins. The mutant proteins polymerized into filaments more readily than wildtype tau, leading to decreased ability to bind wildtype tau. Using proteomic analysis, David et al. (2005) showed that expression of human P301L mutant tau in transgenic mice resulted in distinct modifications of the brain proteome, suggesting alterations in the mitochondrial electron transport chain, cellular antioxidant capacities, and synaptic properties. Subsequent examination of complex V levels in brains of FTDP17 patients carrying the P301L tau mutation confirmed the observations made in P301L tau transgenic mice and suggested that P301L mutant tau pathology caused a specific mitochondrial dysfunction in humans and mice. In agreement, transgenic P301L tau mice exhibited an initial defect in mitochondrial function with reduced complex I activity, which, with age, translated into a mitochondrial respiration deficiency with diminished ATP synthesis corresponding to reduced complex V activity. P301L mutant tau also caused higher oxidative stress, modified lipid peroxidation levels, and upregulated antioxidant enzyme activities, without reducing mitochondrial numbers or significantly changing transport of mitochondria along neurites. In addition, P301L mutant tau decreased the membrane potential of cortical brain cells in transgenic mice, as these cells became more susceptible to A-beta treatment. Using purified recombinant proteins, Aoyagi et al. (2007) showed that P301L mutant tau assembled into nuclei more rapidly than wildtype tau or R406W (157140.0003) mutant tau. However, P301L mutant nuclei could only promote assembly of P301L mutant tau into filaments, whereas wildtype and R406W mutant nuclei had the ability to seed both wildtype and P301L mutant tau. Pronase digestion experiments revealed conformational differences between P301L mutant tau and wildtype or R406W mutant tau. The core structure of P301L mutant tau seeds was distinct from that of wildtype tau seeds, regardless of phosphorylation state, whereas R406W mutant tau seeds had a core structure similar to that of wildtype tau seeds. Donker Kaat et al. (2009) identified a P301L mutation in 1 of 172 probands with progressive supranuclear palsy (601104). (less)

In a large Dutch kindred with frontotemporal dementia (600274) reported by Heutink et al. (1997), Hutton et al. (1998) found a pro301-to-leu mutation (P301L) in exon 10 of the MAPT gene. The same mutation was found in a small kindred from the United States. This substitution occurred in a highly conserved region of the MAPT sequence, where a proline residue was found in all mammalian species from which tau had been cloned to that time. The P301L mutation would affect only the 4-repeat tau isoforms because exon 10 is spliced out of mRNA that encodes the 3-repeat isoforms. Analysis of tau aggregates in affected brains from the U.S. kindred revealed that these consist mainly of 4-repeat isoforms, consistent with the mutation affecting exon 10. In a note added in proof, Poorkaj et al. (1998) described finding a C-to-T transition at nucleotide 728 of the MAPT gene in a newly ascertained family with FTDP17. The mutation resulted in a PRO243LEU mutation. This is the same mutation as that reported by Hutton et al. (1998), who used a different numbering system for the nucleotides and codons. At the time the paper of Poorkaj et al. (1998) was submitted, the longest amino acid form of tau in the database did not include all of the alternatively spliced exons (Poorkaj, 1998). MAPT transcripts that contain this exon 10 mutation encode tau isoforms with 4 microtubule (MT)-binding repeats (4Rtau) as opposed to tau isoforms with 3 MT-binding repeats (3Rtau). Clark et al. (1998) found that brains of patients with the P301L missense mutation contained aggregates of insoluble 4Rtau in filamentous inclusions, which may lead to neurodegeneration. Using purified recombinant proteins, Alonso et al. (2004) showed that several FTDP17-associated tau mutations, including P301L, made tau a more favorable substrate for abnormal hyperphosphorylation compared with wildtype tau. Both the phosphorylation kinetics, due to induced conformational changes, and the phosphorylation stoichiometry, due to increased phosphorylation of more than a single site, were more favorable in the mutant proteins. The mutant proteins polymerized into filaments more readily than wildtype tau, leading to decreased ability to bind wildtype tau. Using proteomic analysis, David et al. (2005) showed that expression of human P301L mutant tau in transgenic mice resulted in distinct modifications of the brain proteome, suggesting alterations in the mitochondrial electron transport chain, cellular antioxidant capacities, and synaptic properties. Subsequent examination of complex V levels in brains of FTDP17 patients carrying the P301L tau mutation confirmed the observations made in P301L tau transgenic mice and suggested that P301L mutant tau pathology caused a specific mitochondrial dysfunction in humans and mice. In agreement, transgenic P301L tau mice exhibited an initial defect in mitochondrial function with reduced complex I activity, which, with age, translated into a mitochondrial respiration deficiency with diminished ATP synthesis corresponding to reduced complex V activity. P301L mutant tau also caused higher oxidative stress, modified lipid peroxidation levels, and upregulated antioxidant enzyme activities, without reducing mitochondrial numbers or significantly changing transport of mitochondria along neurites. In addition, P301L mutant tau decreased the membrane potential of cortical brain cells in transgenic mice, as these cells became more susceptible to A-beta treatment. Using purified recombinant proteins, Aoyagi et al. (2007) showed that P301L mutant tau assembled into nuclei more rapidly than wildtype tau or R406W (157140.0003) mutant tau. However, P301L mutant nuclei could only promote assembly of P301L mutant tau into filaments, whereas wildtype and R406W mutant nuclei had the ability to seed both wildtype and P301L mutant tau. Pronase digestion experiments revealed conformational differences between P301L mutant tau and wildtype or R406W mutant tau. The core structure of P301L mutant tau seeds was distinct from that of wildtype tau seeds, regardless of phosphorylation state, whereas R406W mutant tau seeds had a core structure similar to that of wildtype tau seeds. Donker Kaat et al. (2009) identified a P301L mutation in 1 of 172 probands with progressive supranuclear palsy (601104). (less)