0 9 Molecular molecular JJ 10 15 basis basis NN 16 18 of of IN 19 20 a a DT 21 29 multiple multiple JJ 30 40 lymphokine lymphokine NN 41 51 deficiency deficiency NN 52 54 in in IN 55 56 a a DT 57 64 patient patient NN 65 69 with with IN 70 76 severe severe JJ 77 85 combined combined JJ 86 102 immunodeficiency immunodeficiency NN 102 103 . . . 105 107 We we PRP 108 112 have have VBP 113 123 previously previously RB 124 132 reported report VBN 133 137 that that IN 138 141 the the DT 142 143 T t NN 144 155 lymphocytes lymphocyte NNS 156 158 of of IN 159 160 a a DT 161 166 child child NN 167 171 with with IN 172 178 severe severe JJ 179 187 combined combined JJ 188 204 immunodeficiency immunodeficiency NN 205 208 are be VBP 209 218 defective defective JJ 219 221 in in IN 222 225 the the DT 226 239 transcription transcription NN 240 242 of of IN 243 250 several several JJ 251 261 lymphokine lymphokine NN 262 267 genes gene NNS 268 272 that that WDT 273 280 include include VBP 281 284 IL2 il2 NN 284 285 , , , 286 289 IL3 IL3 NNP 289 290 , , , 291 294 IL4 IL4 NNP 294 295 , , , 296 299 and and CC 300 303 IL5 IL5 NNP 303 304 , , , 305 310 which which WDT 311 317 encode encode VBP 318 330 interleukins interleukin NNS 331 332 2 2 CD 332 333 , , , 334 335 3 3 CD 335 336 , , , 337 338 4 4 CD 338 339 , , , 340 343 and and CC 344 345 5 5 CD 346 347 ( ( ( 347 351 IL-2 IL-2 NNP 351 352 , , , 353 355 -3 -3 CD 355 356 , , , 357 359 -4 -4 CD 359 360 , , , 361 364 and and CC 365 367 -5 -5 CD 367 368 ) ) ) 368 369 . . . 370 372 To to TO 373 382 determine determine VB 383 390 whether whether IN 391 394 the the DT 395 401 defect defect NN 402 404 in in IN 405 408 the the DT 409 416 patient patient NN 416 418 ’s 's POS 419 420 T t NN 421 432 lymphocytes lymphocyte NNS 433 441 involved involve VBD 442 443 a a DT 444 456 trans-acting trans-acting JJ 457 463 factor factor NN 464 470 common common JJ 471 473 to to TO 474 477 the the DT 478 486 affected affect VBN 487 497 lymphokine lymphokine NN 498 503 genes gene NNS 503 504 , , , 505 507 we we PRP 508 516 examined examine VBD 517 520 the the DT 521 528 ability ability NN 529 531 of of IN 532 539 nuclear nuclear JJ 540 547 factors factor NNS 548 552 from from IN 553 556 the the DT 557 564 patient patient NN 564 566 ’s 's POS 567 568 T t NN 569 580 lymphocytes lymphocyte NNS 581 583 to to TO 584 588 bind bind VB 589 597 response response NN 598 606 elements element NNS 607 614 present present JJ 615 617 in in IN 618 621 the the DT 622 632 regulatory regulatory JJ 633 639 region region NN 640 642 of of IN 643 646 IL2 il2 NN 646 647 . . . 648 655 Nuclear nuclear JJ 656 662 factor factor NN 663 668 NF-kB NF-kB NNP 668 669 , , , 670 680 activation activation NN 681 688 protein protein NN 689 690 1 1 CD 691 692 ( ( ( 692 696 AP-1 ap-1 NN 696 697 ) ) ) 697 698 , , , 699 704 OCT-1 OCT-1 NNP 704 705 , , , 706 709 and and CC 710 718 NF-IL-2B NF-IL-2B NNP 719 726 binding binding NN 727 735 activity activity NN 736 740 were be VBD 741 747 normal normal JJ 747 748 . . . 749 751 In in IN 752 760 contrast contrast NN 760 761 , , , 762 765 the the DT 766 773 binding binding NN 774 776 of of IN 777 780 the the DT 781 788 nuclear nuclear JJ 789 795 factor factor NN 796 798 of of IN 799 808 activated activate VBN 809 810 T t NN 811 816 cells cell NNS 817 818 ( ( ( 818 823 NF-AT NF-AT NNP 823 824 ) ) ) 825 827 to to TO 828 831 its its PRP$ 832 840 response response NN 841 848 element element NN 849 851 in in IN 852 855 the the DT 856 859 IL2 il2 NN 860 868 enhancer enhancer NN 869 872 and and CC 873 875 to to TO 876 878 an an DT 879 889 NF-AT-like nf-at-like JJ 890 898 response response NN 899 906 element element NN 907 914 present present JJ 915 917 in in IN 918 921 the the DT 922 925 IL4 il4 NN 926 934 enhancer enhancer NN 935 938 was be VBD 939 947 abnormal abnormal JJ 947 948 . . . 949 951 To to TO 952 961 ascertain ascertain VB 962 969 whether whether IN 970 973 the the DT 974 982 abnormal abnormal JJ 983 988 NF-AT nf-at NN 989 996 binding binding NN 997 1005 activity activity NN 1006 1009 was be VBD 1010 1017 related relate VBN 1018 1020 to to TO 1021 1023 an an DT 1024 1032 impaired impaired JJ 1033 1041 function function NN 1041 1042 , , , 1043 1045 we we PRP 1046 1057 transfected transfecte VBD 1058 1065 patient patient NN 1066 1069 and and CC 1070 1077 control control NN 1078 1079 T t NN 1080 1091 lymphocytes lymphocyte NNS 1092 1096 with with IN 1097 1107 constructs construct NNS 1108 1118 containing contain VBG 1119 1122 the the DT 1123 1131 reporter reporter NN 1132 1136 gene gene NN 1137 1145 encoding encode VBG 1146 1161 chloramphenicol chloramphenicol NN 1162 1168 acetyl acetyl NN 1169 1180 transferase transferase NN 1181 1182 ( ( ( 1182 1185 CAT CAT NNP 1185 1186 ) ) ) 1187 1192 under under IN 1193 1196 the the DT 1197 1204 control control NN 1205 1207 of of IN 1208 1211 the the DT 1212 1218 entire entire JJ 1219 1222 IL2 il2 NN 1223 1233 regulatory regulatory JJ 1234 1240 region region NN 1241 1243 or or CC 1244 1246 of of IN 1247 1256 multimers multimer NNS 1257 1259 of of IN 1260 1270 individual individual JJ 1271 1279 enhancer enhancer NN 1280 1289 sequences sequence NNS 1289 1290 . . . 1291 1294 CAT CAT NNP 1295 1305 expression expression NN 1306 1314 directed direct VBN 1315 1317 by by IN 1318 1321 the the DT 1322 1325 IL2 il2 NN 1326 1336 regulatory regulatory JJ 1337 1343 region region NN 1344 1346 or or CC 1347 1349 by by IN 1350 1351 a a DT 1352 1360 multimer multimer NN 1361 1363 of of IN 1364 1367 the the DT 1368 1381 NF-AT-binding nf-at-binding JJ 1382 1386 site site NN 1387 1390 was be VBD 1391 1399 markedly markedly RB 1400 1405 lower low JJR 1406 1408 in in IN 1409 1412 the the DT 1413 1420 patient patient NN 1421 1429 relative relative JJ 1430 1432 to to TO 1433 1441 controls control NNS 1441 1442 . . . 1443 1445 In in IN 1446 1454 contrast contrast NN 1454 1455 , , , 1456 1459 CAT CAT NNP 1460 1464 gene gene NN 1465 1475 expression expression NN 1476 1484 directed direct VBN 1485 1487 by by IN 1488 1489 a a DT 1490 1498 multimer multimer NN 1499 1501 of of IN 1502 1505 the the DT 1506 1511 OCT-1 oct-1 NN 1512 1520 proximal proximal JJ 1521 1522 ( ( ( 1522 1537 OCT-1p)-binding oct-1p)-binding JJ 1538 1542 site site NN 1543 1546 was be VBD 1547 1557 equivalent equivalent JJ 1558 1560 in in IN 1561 1568 patient patient NN 1569 1572 and and CC 1573 1581 controls control NNS 1581 1582 . . . 1583 1588 These these DT 1589 1596 results result NNS 1597 1605 indicate indicate VBP 1606 1610 that that IN 1611 1613 an an DT 1614 1625 abnormality abnormality NN 1626 1631 of/or of/or IN 1632 1643 influencing influence VBG 1644 1649 NF-AT NF-AT NNP 1650 1653 may may MD 1654 1662 underlie underlie VB 1663 1666 the the DT 1667 1675 multiple multiple JJ 1676 1686 lymphokine lymphokine NN 1687 1697 deficiency deficiency NN 1698 1700 in in IN 1701 1705 this this DT 1706 1713 patient patient NN 1713 1714 . . .