0 8 Mutation mutation NN 9 11 of of IN 12 16 Jak3 jak3 NN 17 19 in in IN 20 21 a a DT 22 29 patient patient NN 30 34 with with IN 35 39 SCID SCID NNP 39 40 : : : 41 50 essential essential JJ 51 55 role role NN 56 58 of of IN 59 63 Jak3 jak3 NN 64 66 in in IN 67 75 lymphoid lymphoid JJ 76 87 development development NN 87 88 . . . 90 95 Males Male NNPS 96 100 with with IN 101 109 X-linked x-linked JJ 110 116 severe severe JJ 117 125 combined combined JJ 126 142 immunodeficiency immunodeficiency NN 143 144 ( ( ( 144 149 XSCID XSCID NNP 149 150 ) ) ) 151 155 have have VBP 156 163 defects defect NNS 164 166 in in IN 167 170 the the DT 171 177 common common JJ 178 186 cytokine cytokine NN 187 195 receptor receptor NN 196 201 gamma gamma NN 202 207 chain chain NN 208 209 ( ( ( 209 214 gamma gamma NN 215 216 c c NN 216 217 ) ) ) 218 222 gene gene NN 223 227 that that WDT 228 235 encodes encode VBZ 236 237 a a DT 238 244 shared shared JJ 244 245 , , , 246 255 essential essential JJ 256 265 component component NN 266 268 of of IN 269 272 the the DT 273 282 receptors receptor NNS 283 285 of of IN 286 299 interleukin-2 interleukin-2 NN 300 301 ( ( ( 301 305 IL-2 il-2 NN 305 306 ) ) ) 306 307 , , , 308 312 IL-4 il-4 NN 312 313 , , , 314 318 IL-7 IL-7 NNP 318 319 , , , 320 324 IL-9 IL-9 NNP 324 325 , , , 326 329 and and CC 330 335 IL-15 IL-15 NNP 335 336 . . . 337 340 The the DT 341 346 Janus Janus NNP 347 353 family family NN 354 362 tyrosine tyrosine NN 363 369 kinase kinase NNP 370 374 Jak3 Jak3 NNP 375 377 is be VBZ 378 381 the the DT 382 386 only only RB 387 396 signaling signal VBG 397 405 molecule molecule NN 406 411 known know VBN 412 414 to to TO 415 417 be be VB 418 428 associated associate VBN 429 433 with with IN 434 439 gamma gamma NN 440 441 c c NN 441 442 , , , 443 445 so so IN 446 448 it it PRP 449 452 was be VBD 453 465 hypothesized hypothesize VBN 466 470 that that IN 471 478 defects defect NNS 479 481 in in IN 482 486 Jak3 Jak3 NNP 487 492 might might MD 493 498 cause cause VB 499 501 an an DT 502 512 XSCID-like xscid-like JJ 513 522 phenotype phenotype NN 522 523 . . . 524 525 A a DT 526 530 girl girl NN 531 535 with with IN 536 549 immunological immunological JJ 550 558 features feature NNS 559 576 indistinguishable indistinguishable JJ 577 581 from from IN 582 587 those those DT 588 590 of of IN 591 596 XSCID XSCID NNP 597 600 was be VBD 601 610 therefore therefore RB 611 619 selected select VBN 620 623 for for IN 624 632 analysis analysis NN 632 633 . . . 634 636 An an DT 637 649 Epstein-Barr epstein-barr JJ 650 655 virus virus NN 656 657 ( ( ( 657 673 EBV)-transformed ebv)-transformed JJ 674 678 cell cell NN 679 683 line line NN 684 691 derived derive VBN 692 696 from from IN 697 700 her her PRP$ 701 712 lymphocytes lymphocyte NNS 713 716 had have VBD 717 723 normal normal JJ 724 729 gamma gamma NN 730 731 c c NN 732 742 expression expression NN 743 746 but but CC 747 753 lacked lack VBD 754 758 Jak3 jak3 NN 759 766 protein protein NN 767 770 and and CC 771 774 had have VBD 775 782 greatly greatly RB 783 793 diminished diminish VBN 794 798 Jak3 jak3 NN 799 808 messenger messenger NN 809 812 RNA RNA NNP 812 813 . . . 814 824 Sequencing Sequencing NNP 825 833 revealed reveal VBD 834 835 a a DT 836 845 different different JJ 846 854 mutation mutation NN 855 857 on on IN 858 862 each each DT 863 869 allele allele NN 869 870 : : : 871 872 a a DT 873 879 single single JJ 880 890 nucleotide nucleotide NN 891 900 insertion insertion NN 901 910 resulting result VBG 911 913 in in IN 914 915 a a DT 916 921 frame frame NN 922 927 shift shift NN 928 931 and and CC 932 941 premature premature JJ 942 953 termination termination NN 954 956 in in IN 957 960 the the DT 961 965 Jak3 jak3 NN 966 969 JH4 jh4 NN 970 976 domain domain NN 977 980 and and CC 981 982 a a DT 983 991 nonsense nonsense JJ 992 1000 mutation mutation NN 1001 1003 in in IN 1004 1007 the the DT 1008 1012 Jak3 jak3 NN 1013 1016 JH2 jh2 NN 1017 1023 domain domain NN 1023 1024 . . . 1025 1028 The the DT 1029 1033 lack lack NN 1034 1036 of of IN 1037 1041 Jak3 jak3 NN 1042 1052 expression expression NN 1053 1063 correlated correlate VBD 1064 1068 with with IN 1069 1077 impaired impaired JJ 1078 1079 B B NNP 1080 1084 cell cell NN 1085 1094 signaling signaling NN 1094 1095 , , , 1096 1098 as as IN 1099 1111 demonstrated demonstrate VBN 1112 1114 by by IN 1115 1118 the the DT 1119 1128 inability inability NN 1129 1131 of of IN 1132 1136 IL-4 il-4 NN 1137 1139 to to TO 1140 1148 activate activate VB 1149 1154 Stat6 Stat6 NNP 1155 1157 in in IN 1158 1161 the the DT 1162 1177 EBV-transformed ebv-transformed JJ 1178 1182 cell cell NN 1183 1187 line line NN 1188 1192 from from IN 1193 1196 the the DT 1197 1204 patient patient NN 1204 1205 . . . 1206 1211 These these DT 1212 1224 observations observation NNS 1225 1233 indicate indicate VBP 1234 1238 that that IN 1239 1242 the the DT 1243 1252 functions function NNS 1253 1255 of of IN 1256 1261 gamma gamma NN 1262 1263 c c NN 1264 1267 are be VBP 1268 1277 dependent dependent JJ 1278 1280 on on IN 1281 1285 Jak3 Jak3 NNP 1286 1289 and and CC 1290 1294 that that IN 1295 1299 Jak3 jak3 NN 1300 1302 is be VBZ 1303 1312 essential essential JJ 1313 1316 for for IN 1317 1325 lymphoid lymphoid JJ 1326 1337 development development NN 1338 1341 and and CC 1342 1351 signaling signaling NN 1351 1352 . . .