A schematic representation of the human tau gene, mRNA and protein isoforms. The human tau gene is located on chromosome 17q21 and contains 16 exons (panel B). White boxes represent constitutive exons and the gray or colored boxes represent alternatively spliced exons. Identified mutations in exons 1–13, and intron 10, of the tau gene are shown using the numbering of the 441-amino acid isoform of tau (panel A). Exon -1 is part of the promoter and is transcribed but not translated, as is the case for exon 14 (panel C). Exons 4A, 6 and 8 are not transcribed in human. Exons 2, 3 and 10 are alternatively spliced, as demonstrated by the different lines linking these exons (panel C), generating a total of 6 different mRNAs which are translated into six different tau isoforms (panel D). These isoforms differ by the absence or presence of one or two N-terminal inserts encoded by exon 2 (orange box) and 3 (yellow box), as well as the presence of either three or four repeat regions coded by exons 9, 10, 11 and 12 (black boxes) in the C-terminus. The second repeat, encoded by exon 10, is highlighted in green. Panel E indicates sites in the acidic, proline-rich, repeat and C-terminal regions of tau reported to be phosphorylated in vivo or in vitro.