ClinVar Genomic variation as it relates to human health

Poorkaj et al. (1998) identified 9 DNA sequence variants in 2 families with what they referred to as FTDP17 (600274); 8 of these were also identified in controls and were thus considered polymorphisms. The ninth variant, VAL279MET, was found in 1 FTDP17 family, but not in the other. (This mutation is designated val337 to met in the numbering used by Hutton et al. (1998); see 157140.0001.) The change was considered positive since it occurred in a highly conserved residue and a normal valine is found at this position in all 3 tau interrepeat sequences and in other MAPT homologs. Furthermore, the mutation cosegregated with the disease in the family and was not found in normal controls. At the time that 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). Using purified recombinant proteins, Alonso et al. (2004) showed that several FTDP17-associated tau mutations, including V337M, 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. Sohn et al. (2019) found that the FTD-associated tau V337M mutant shortened the axon initial segment (AIS) and impaired AIS plasticity in human induced pluripotent stem cell (iPSC)-derived neurons. Electrophysiologic properties of tau V337M neurons revealed that the mutation also impaired homeostatic control of spontaneous neuronal activity in response to depolarization. End-binding protein-3 (EB3, or MAPRE3; 605788), a component of the AIS cytoskeleton, was associated with ANKG (106280) and tau in the AIS submembrane region of human neurons. However, the V337M mutation increased the binding affinity of tau with EB3, leading to increased EB3 accumulation in the AIS in tau V337M mutant neurons. EB3 accumulation increased its interaction with ANKG and promoted its structural stability via physical interaction with microtubules, thereby impairing AIS plasticity in tau V337M mutant neurons. (less)