table

Numbering according to the longest isoform of 441 AA (Nomemclature selon l'isoforme la plus longue (441 acides aminés))

1 M (Met) (N terminal)

2 A (Ala)

3 E (Glu)

4 P (Pro)

5 R (Arg)  Mutation reported (4R tau aggregates) Ann Neurol 2002 Apr;51(4):525-30                     R5L also

6 Q (Gln)

7 E (Glu)

8 F (Phe)

9 E (Glu)

10 V (Val)

11 M (Met)

12 E (Glu)

13 D (Asp)

14 H (His)

15 A (Ala)

16 G (Gly)

17 T (Thr)

18 Y (Tyr)

19 G (Gly)

20 L (Leu)

21 G (Gly)

22 D (Asp)

23 R (Arg)

24 K (Lys)

25 D (Asp)

26 Q (Gln)

27 G (Gly)

28 G (Gly)

29 Y (Tyr)

30 T (Thr)

31 M (Met)

32 H (His)

33 Q (Gln)

34 D (Asp)

35 Q (Gln)

36 E (Glu)

37 G (Gly)

38 D (Asp)

39 T (Thr)

40 D (Asp)

41 A (Ala)

42 G (Gly)

43 L (Leu)

44 K (Lys) END EXON 1

intron: gttagtggac..........................

45 E

46 S

47 P(Pro)

48 L

49 Q

50 T

51 P(Pro)

52 T

53 E

54 D

55 G

56 S

57 E

58 E

59 P(Pro)

60 G

61 S

62 E

63 T

64 S

65 D

66 A

67 K

68 S

69 T

70 P(Pro)

71 T

72 A

73 E End exon 2

74 D

75 V

76 T

77 A

78 P(Pro)

79 L

80 V

81 D

82 E

83 G

84 A

85 P(Pro)

86 G

87 K

88 Q (Gln)

89 A

90 A

91 A

92 Q (Gln)

93 P(Pro)

94 H

95 T

96 E

97 I

98 P(Pro)

99 E

100 G

101 T

102 T End EXON 3

103 A (Ala)

104 E (Glu)

105 E (Glu)

106 A (Ala)

107 G (Gly)

108 I (Ile)

109 G (Gly)

110 D (Asp)

111 T (Thr)

112 P (Pro)

113 S (Ser)

114 L (Leu)

115 E (Glu)

116 D (Asp)

117 E (Glu)

118 A (Ala)

119 A (Ala)

120 G (Gly)

121 H (His)

122 V (Val)

123 T (Thr)

124 Q (Gln) End exon 4

125 A (Ala)

126 R (Arg)

127 M (Met)

128 V (Val)

129 S (Ser)

130 K (Lys)

131 Ser

132 K (Lys)

133 D (Asp)

134 G (Gly)

135 T (Thr)

136 G (Gly)

137 Ser

138 D (Asp)

139 D (Asp)

140 K (Lys)

141 K (Lys)

142 A (Ala)

143 K (Lys) End exon5

144 G (Gly)

145 A (Ala)

146 D (Asp)

147 G (Gly)

148 K (Lys)

149 T (Thr)

150 K (Lys)

151 I (Ile)

152 A (Ala)

153 T (Thr)

154 P (Pro)**

155 R (Arg)

156 G (Gly)

157 A (Ala)

158 A (Ala)

159 P (Pro)

160 P (Pro

161 G (Gly)

162 Q (Gln)

163 K (Lys)

164 G (Gly)

165 E (Glu)

166 A (Ala)

167 N (Asn)

168 A (Ala)

169 T (Thr)

170 R (Arg)

171 I (Ile)

172 P (Pro)

173 A (Ala)

174 K (Lys)

175 T (Thr)

176 P (Pro)

177 P (Pro)

178 A (Ala)

179 P (Pro)

180 K (Lys)

181 T (Thr) 

182 P (Pro)

183 P (Pro)

184 Ser

185 Ser End exon7

186 G (Gly) start exon 9

187 E (Glu)

188 P (Pro)

189 P (Pro)

190 K (Lys)

191 Ser

192 G (Gly)

193 D (Asp)

194 R (Arg)

195 Ser

196 G (Gly)

197 Y (Tyr)

198 Ser

199 Ser

200 P (Pro)

201 G (Gly)

202 Ser

203 P (Pro)

204 G (Gly)

205 T (Thr)

206 P (Pro)

207 G (Gly)

208 Ser

209 R (Arg)

210 Ser

211 R (Arg)

212 T (Thr)

213 P (Pro)

214 Ser

215 L (Leu)

216 P (Pro)

217 T (Thr)

218 P (Pro)

219 P (Pro)

220 T (Thr)

221 R (Arg)

222 E (Glu)

223 P (Pro)

224 K (Lys) KKVAVVR: interaction with the 3R/4R region

225 K (Lys) This interaction participates to the conformation

226 V (Val)

227 A (Ala)

228 V (Val)

229 V (Val)

230 R (Arg)

231 T (Thr)

232 P (Pro)

233 P (Pro)

234 K (Lys)

235 Ser

236 P (Pro)

237 Ser

238 Ser

257 K (Lys) Mutation K257T: decrease of tau binding; aggregation of 3R tau >4R; inclusions: Pick bodies (Spillantini et al; Hutton et al ..)

266 L (Leu)  L266V: Pick-like tau pathology (Hogg et al 2003; Kobayashi et al

269 Q (Gln)

270 P (Pro)*

271 G (Gly)

272 G (Gly) Mutation G272V Families HFTD II: Pick-like bodies (Spillantini et al, Am J Pathol 1998,153:1359-1363); decreases microtubule stability: Rizzu et al, Am J Human Genet, 1999,64:414-421; Hasegawa et al, 1998, FEBS Letters, 437:207-210

273 G (Gly)

274 K (Lys) End exon9

279 N (Asn)-> N279K: Mutation does not modify tau-tubulin interaction, but acts on exon 10 splicing: Hasegawa et al, Febs Letters, 199,443:93-96; D'Souza et al, PNAS, 1999, 96:5598-5602

Lesions with tau exon 10+ isoforms(Tau 64 et 69): Clark et al, PNAS, 1998,95:13103-13107. PSP phenotype

N279K: clinical pattern

280 K (Lys)Mutation deltaK280 deletion of lysine: decreases microtubules stability: Rizzu et al, Am J Human Genet, 1999, 64:414-421; Mutation acts first on exon 10 splicing: D'Souza et al, PNAS, 1999, 96:5598-5602

281 K (Lys)

282 L (Leu)

283 D (Asp)

L284 L (Leu) This mutation acts on exon 10 splicing: D'Souza et al, PNAS, 1999, 96:5598-5602. Amyloid deposits

285 Ser

286 N (Asn)

287 V (Val) Repeat 2

288 Q (Gln)

289 Ser

290 K (Lys)

291 C (Cys) possible disulfide bridge with Cys322 for tau 4R isoforms.

292 G (Gly)

293 Ser

294 K (Lys)

295 D (Asp)

296 N (Asn) mutation ; Delta N 296

297 I (Ile)

298 K (Lys)

299 H (His)

300 V (Val)

301 P (Pro) to Mutations Leu or Ser...strongly inhibits the polymerisation of microtubules. Families HFTD I (Seatle D,F ; Oregon E,L. Neuron and glial tangles. Twisted ribbons of tau,essentially E10+ (Tau 64 et 69): Spillantini et al, Am J Pathol 1998,153:1359-1363 ; Clark et al, PNAS, 1998,95:13103-13107 ; Mirra et al, JNEN, 1998,58:335-345

P301L: clinical pattern

This mutation provokes destabilisation of tau and its aggregation: Nacharaju et al, FEBS 1999,447:195-199 ; dicreases microtubule stability: Rizzu et al, Am J Human Genet, 1999,64:414-421; Hasegawa et al, 1998, FEBS Letters, 437:207-210; Nacharaju et al, FEBS Lett, 1999,447:195-199, suggesting that other factors modulate clinical and neuropathological expression (Bird et al, Brain 1999, 12:741-756

Patterns with the upper tau doublet in the frontal cortex and the triplet in the temporal and parietal cortex (van Swieten et al, Ann Neurol, 1999,46:617-626)

P301S: specificity: seizures; Lossos A et al J Neurol  2003 Jun;250(6):733-40

302 G (Gly)

303 G (Gly) ->V Ros R, A new mutation of the tau gene, G303V, in early-onset familial progressive supranuclear palsy., Arch Neurol 2005 Sep;62(9):1444-5

304 G (Gly)

305 Ser Mutation Ser305Asn: Iijima et al, Neuroreport 1999,10:497-501: Japonese family. Frontotemporal dementia, low Parkinsonism. Tangles in neurones made up of straight tubules , found mainly in cortical layer II. Tangles in astrocytes of the cortical ans subcortical white matter

This mutation does not modify tau-tubulin interaction, but acts on exon 10 splicing: Hasegawa et al, Febs Letters, 199, 443:93-96 .

Early memory loss

-------------------------End exon 10: intron 10------------------------

Intron that regulates splicing of exon 10: many mutations in this intronic region provoke FTDP-17.

Mutations +3,+12,+13,+14,+16, +33: modification of a stem loop of messager RNA that abnormally increases the expression of tau E10+ isoforms.

  +3: Early memory loss

+11: mental reatardation

Mutation +16: clinical picture

-----------------Exon 11

306 V (Val)

307 Q (Gln)

308 I (Ile)

309 V (Val)

310 Y (Tyr)

311 K (Lys)

312 P (Pro)** R2-R3 IR

313 V (Val)

314 D (Asp)

315 L (Leu)     L315R (van Herpen et al,2002)

316 Ser

317 K (Lys)

318 V (Val) R3

319 T (Thr)

320 Ser     S320F

A novel tau mutation, S320F, causes a tauopathy with inclusions similar to those in Pick's disease.
Ann Neurol. 2002 Mar;51(3):373-6.

321 K (Lys)

322 C (Cys) Oxydation of this cysteine provokes tau aggregation (Schweers et al 1995), specially for Tau 3R, since 4R canhave a disulfide bridge with Cys291 that prevents oxydation

323 G (Gly)

324 Ser

325 L (Leu)

326 G (Gly)

327 N (Asn)

328 I (Ile)

329 H (His)

330 H (His)

331 K (Lys)

332 P (Pro)* End exon 11

Exon 12

333 G (Gly)

334 G (Gly)

335 G (Gly)

336 Q (Gln) R3-R4 IR Pickering-Brown SM et al, Brain 2004

337 V (Val) Mutation V337M GTG->ATG Families Seatle A, 6 isoforms. PHF

This mutation provokes microtubule destabilisation and tau aggregation: Nacharaju et al, FEBS 1999,447:195-199 ; dicreases microtubules stability: Hasegawa et al, 1998, FEBS Letters, 437:207-210; Nacharaju et al, FEBS Lett, 1999,447:195-199; Arawaka et al, 1999, Neuroreport, 10:993-997
This mutation provokes a loss of function of the tau isoforms without exon 10. It shows that mutations located on the six tau isoforms (because the mutation is located in a region common to all six isoforms) can have essentially a physiological defect on only 3 of the six isoforms. It explains the heterogeneous eeffet of tau mutation (Sahara et al, J Neurosci Res, 2000, 60:380-387).

339 V (Val)

340 K (Lys)

341 Ser

342 E (Glu) mutation Val: 4R tauopathy essentiall

343 K (Lys) R3-R4 IR

344 L (Leu) h

345 D (Asp)

346 F (Phe)

347 K (Lys)

348 D (Asp)

349 R (Arg)

350 V (Val) R4

351 Q (Gln)

352 Ser

353 K (Lys)

354 I (Ile)

355 G (Gly)

356 Ser

357 L (Leu)

358 D (Asp)

359 N (Asn)

360 I (Ile)

361 T (Thr)

362 H (His)

363 V (Val)

364 P (Pro)

365 G (Gly)

366 G (Gly)

367 G (Gly)

368 N (Asn)

369 K (Lys) mutation K369 I: Pick phenotype

370 K (Lys) fin exon 12

371 I (Ile)

372 E (Glu)

373 T (Thr)

374 H (His)

375 K (Lys)

376 L (Leu)

377 T (Thr)

378 F (Phe)

379 R (Arg)

380 E (Glu)

381 N (Asn)

382 A (Ala)

383 K (Lys)

384 A (Ala)

385 K (Lys)

386 T (Thr)

387 D (Asp)

388 H (His)

389 G (Gly) Mutation G389R

Murell et al, JNEN, 1999,58:1227_1233. Provokes a "Pick-like" pathology

390 A (Ala)

391 E (Glu)

392 I (Ile)

393 V (Val)

394 Y (Tyr)

395 K (Lys)

396 Ser         AD2 phosporylation site

397 P (Pro)**

398 V (Val)

399 V (Val)

400 Ser

401 G (Gly)

402 D (Asp)

403 T (Thr)

404 Ser  AD2 phosphorylation site

405 P (Pro)**

406 R (Arg)Mutation R406W: Iowa family. Mutation decreases microtubule stability: Rizzu et al, Am J Human Genet, 1999, 64:414-421 ; Hasegawa et al, 1998, FEBS Letters, 437:207-210; Nacharaju et al, FEBS Lett, 1999,447:195-199
.
Affects more specifically tau isoforms with 3R: Sahara et al, J. Neuroscience Research, 60:380-387, 2000.

PSP phenotype. Early memory loss

407 H (His)

408 L (Leu)

409 Ser

410 N (Asn)

411 V (Val)

412 Ser

413 Ser

414 T (Thr)

415 G (Gly)

416 Ser

417 I (Ile)

418 D (Asp)

419 M (Met)

420 V (Val)

421 D (Asp)

422 Ser

423 P (Pro)**

424 Q (Gln)

425 L (Leu)

426 A (Ala)

427 T (Thr)

428 L (Leu)

429 A (Ala)

430 D (Asp)

431 E (Glu)

432 V (Val)

433 Ser

434 A (Ala)

435 Ser

436 L (Leu)

437 A (Ala)

438 K (Lys)

439 Q (Gln)

440 G (Gly)

441 L (Leu)