ClinVar Genomic variation as it relates to human health

In affected members of a family from the United States with autosomal dominant frontotemporal dementia (600274) originally reported by Reed et al. (1997), Hutton et al. (1998) identified a heterozygous arg406-to-trp mutation (R406W) in the MAPT gene. Neuropathologic examination identified tau-positive intraneuronal neurofibrillary tangles similar to those found in Alzheimer disease (see 104300). Connell et al. (2001) studied the in vitro phosphorylation of several tau mutants by glycogen synthase kinase 3-beta and confirmed previous findings that the R406W mutation had the surprising effect of reducing tau phosphorylation in cells, compared to both the wildtype and other mutant forms. Connell et al. (2001) suggested that reduced tau phosphorylation and a minor loss of function associated with R406W may contribute to the later onset and somewhat milder phenotype found in families with this mutation. Tatebayashi et al. (2002) showed that the expression of the R406W mutation in transgenic mice resulted in the development of congophilic hyperphosphorylated tau inclusions in forebrain neurons. These inclusions appeared as early as 18 months of age. As with human cases, tau inclusions were composed of both mutant and endogenous wildtype tau, and were associated with microtubule disruption and flame-shaped transformations of the affected neurons. Behaviorally, aged transgenic mice had associative memory impairment without obvious sensorimotor deficits. Therefore, these mice exhibited a phenotype mimicking R406W FTDP17 (frontotemporal dementia and parkinsonism linked to chromosome 17). Saito et al. (2002) reported a patient who presented at age 47 years with psychiatric disturbances, primarily delusions, who developed overt dementia by age 52, and died at age 53. There was rapid progression in the last year of life. His father had had a similar illness. Postmortem examination revealed neuronal loss associated with neurofibrillary tangles and neuropil threads, accentuated in the medial temporal lobe, that were immunoreactive for the tau protein. Molecular analysis revealed an R406W mutation. Rademakers et al. (2003) suggested that the R406W mutation can cause a clinical picture closely resembling Alzheimer disease and quite different from frontotemporal dementia with parkinsonism. They described a 6-generation Belgian family that carried the R406W mutation and had such clinical features, and pointed to reports of 2 other families that carried the R406W mutation and had similar clinical characteristics: 1 from the U.S. Midwest with a Danish ancestor (Reed et al., 1997) and 1 from the Netherlands (van Swieten et al., 1999). Haplotype data ruled against a founder effect for the origin of the mutation in western Europe. Rademakers et al. (2003) stated that their report illustrated the phenotypic heterogeneity of MAPT mutations and reemphasized that MAPT should be considered a candidate gene for clinical Alzheimer disease families in which mutations in known Alzheimer disease genes have been excluded. Using purified recombinant proteins, Alonso et al. (2004) showed that several FTDP17-associated tau mutations, including R406W, 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 purified recombinant proteins, Aoyagi et al. (2007) showed that P301L (157140.0001) mutant tau assembled into nuclei more rapidly than wildtype tau or R406W 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. (less)