Mutations of the CD40L gene and CD40L expression in patients with X-linked HIGM
. | . | . | . | . | Protein expression by flow cytometry . | . | . | |
|---|---|---|---|---|---|---|---|---|
| Family/Patient . | Genomic DNA mutation (nucleotide no.)* . | cDNA mutation (nucleotide no.)*if different from gDNA . | Predicted effect on protein . | Affected domain . | Anti-CD40L mAb . | CD40-Ig . | Reference‡ . | |
| Exon 1/Intron 1 | ||||||||
| Nonsense and missense mutations | ||||||||
| 1 | 52C > T | — | Arg 11 stop | IC | + | (+) | 31,35 | |
| 2 | 99T > G† | — | Tyr 26 stop | TM | D | D | ||
| 3 | 128T > G | — | Met 36 Arg | TM | NA | NA | 36 | |
| 4 | 175A > T | — | Lys 52 stop | EC | D | D | ||
| Splice site mutations | ||||||||
| 5 | IVS1 + 1 g > a† | Del 82 bp (nt 96-177) | fs, stop at 26 | TM | D | D | ||
| 6 | IVS1 + 1 g > t | Del 82 bp (nt 96-177) | fs, stop at 26 | TM | D | D | ||
| Del 10 bp (nt 168-177) | fs, stop at 50 | EC | ||||||
| Wild type cDNA | ||||||||
| 7 a,b,c | IVS1 + 1 g > t | Del 82 bp (nt 96-177) | fs, stop at 26 | EC | D | D | 31 | |
| Del 43 bp (nt 135-177) | fs, stop at 39 | EC | ||||||
| Del 10 bp (nt 168-177) | fs, stop at 50 | TM | ||||||
| Del 14 bp (nt 168-181) | fs, stop at 51 | TM | ||||||
| Wild type cDNA | ||||||||
| 8 | IVS1 + 1 g > t | Del 82 bp (nt 96-177) | fs, stop at 26 | TM | D | D | ||
| Wild type cDNA | ||||||||
| Exon2/Intron 2 | ||||||||
| Nonsense mutations | ||||||||
| 9 | 187G > T | — | Glu 56 stop | EC | D | D | 31 | |
| 10 | 229C > T | — | Gln 70 stop | EC | D | D | ||
| Deletions | ||||||||
| 11 | Del 9 bp aatagATAG | 178-81 Del ATAG | fs, stop at 65 | EC | NA | NA | ||
| 12 | Del 8 bp atagATAG | 178-81 Del ATAG | fs, stop at 65 | EC | NA | NA | 31,36 | |
| 13 | Del 8 bp atagATAG | 178-81 Del ATAG | fs, stop at 65 | EC | D | D | ||
| 14 | Del 4 bp ATAG | 178-81 Del ATAG | fs, stop at 65 | EC | NA | NA | ||
| 15 | Del 2 bp CA (229-30) | 229-30 Del CA | fs, stop at 84 | EC | NA | NA | ||
| Splice site mutations | ||||||||
| 16 a,b | IVS2 + 1 g > a | E2 skip | Inframe del 44 aa | EC | + | D | 31,36 | |
| Ins 19 bp (5′ part of 12) | fs, stop at 118 | |||||||
| 17 | IVS2 + 2 t > a | E2 skip | Inframe del 44 aa | EC | + | (+) | 31,35 | |
| Ins 19 bp (5′ part of 12) | fs, stop at 118 | |||||||
| Wild type cDNA | ||||||||
| Exon 3/Intron 3 | ||||||||
| Deletions | ||||||||
| 18 | 344-7 Del A† | A344-7 Del A | fs, stop at 127 | EC | D | D | ||
| Splice site mutations | ||||||||
| 19 | 367G > A | E3 skip (del 310-67) | fs, stop at 108 | EC | + | (+) | 31 | |
| Wild type cDNA | ||||||||
| 20 | 367G > C† | E3 skip (del 310-67) | fs, stop at 108 | EC | D | D | ||
| Lys 96 Asn | ||||||||
| 21 | IVS3 + 1 g > a | E3 skip (del 310-67) | fs, stop at 108 | EC | D | D | ||
| 22 | IVS3 + 1 g > a | E3 skip (del 310-67) | fs, stop at 108 | EC | D | D | ||
| 23 | IVS3 + 1 g > a | E3 skip (del 310-67) | fs, stop at 108 | EC | D | D | ||
| 24 | IVS3 + 1 g Del | E3 skip (del 310-67) | fs, stop at 108 | EC | D | D | ||
| 25 | IVS3 + 2 t > c | E3 skip (del 310-67) | fs, stop at 108 | EC | + | (+) | 31 | |
| Wild type cDNA | ||||||||
| 26 | IVS3 + 5 g > c | E3 skip (del 310-67) | fs, stop at 108 | EC | + | (+) | 31 | |
| Wild type cDNA | ||||||||
| 27 | IVS3-915a > t† | New splice site Ins 59 bp between E3&E4 | fs, stop at 127 | EC(TNF) | D | D | ||
| 28 a,b | IVS3-1 g > a | E4 skip (del 368-430) | Inframe del 21 aa | EC(TNF) | NA | NA | ||
| 29 | IVS3-1 g > c | E4 skip (del 368-430) | Inframe del 21 aa | EC(TNF) | D | NA | ||
| Exon 4/Intron 4 | ||||||||
| Missense mutations | ||||||||
| 30 | 405T > A | — | Ser 128 Arg | EC(TNF) | + | D | 31 | |
| 407A > G | — | Glu 129 Gly | ||||||
| Insertions | ||||||||
| 31 | 403-405 ins G | — | fs, stop at 129 | EC(TNF) | D | D | 31 | |
| 32 | 403-405 ins G | — | fs, stop at 129 | EC(TNF) | D | D | 31 | |
| 33 a,b,c | 411-413 ins A | — | fs, stop at 133 | EC(TNF) | NA | NA | 37 | |
| 34 | 417-422 ins A† | — | fs, stop at 142 | EC(TNF) | NA | NA | ||
| Splice site mutations | ||||||||
| 35 a,b,c,d,e | IVS4 + 1 g > c | E4 skip (del 368-430) | Inframe del 21 aa fs | EC(TNF) | + | D | 31 | |
| Ins 5′ part of IVS4 (23, 73, 152 bp) | ||||||||
| 36 | IVS4 + 1 g > c | E4 skip (del 368-430) | Inframe del 21 aa | EC(TNF) | + | D | 31 | |
| 37 | IVS4 + 1 g > c | E4 skip (del 368-430) | Inframe del 21 aa | EC(TNF) | NA | NA | ||
| 38 | IVS4 + 2 i > c | E4 skip (del 368-430) | Inframe del 21 aa | EC(TNF) | D | NA | ||
| Exon 5/Intron 5 | ||||||||
| Nonsense and missense mutations | ||||||||
| 39 | 436C > T† | — | Gln 139 stop | EC(TNF) | D | D | ||
| 40 | 440G > A | — | Trp 140 stop | EC(TNF) | D | D | 36 | |
| 41 | 456C > A | — | Thy 145 stop | EC(TNF) | D | NA | ||
| 42 | 461C > A | — | Thr 147 Asn | EC(TNF) | + | D | 31 | |
| 43 | 517C > T | — | Gln 166 stop | EC(TNF) | D | D | ||
| 44 a,b | 517C > T | — | Gln 166 stop | EC(TNF) | D | D | ||
| 45 a,b | 526T > G | — | Tyr 169 Asp | EC(TNF) | D | NA | ||
| 46 a,b | 530C > A | — | Tyr 170 Cys | EC(TNF) | D | D | 31 | |
| 47 | 541C > T† | — | Gln 174 stop | EC(TNF) | D | D | ||
| 48 | 577C > T | — | Gln 186 stop | EC(TNF) | D | D | 31 | |
| 49 | 577C > T | — | Gln 186 stop | EC(TNF) | NA | NA | ||
| 50 | 619A > T | — | Arg 200 stop | EC(TNF) | NA | NA | ||
| 51 | 619A > T | — | Arg 200 stop | EC(TNF) | D | D | ||
| 52 | 629G > T† | — | Arg 203 Ile | EC(TNF) | + | D | ||
| 53 | 675C > A | — | Cys 218 stop | EC(TNF) | NA | NA | ||
| 54 | 675C > A | — | Cys 218 stop | EC(TNF) | D | NA | ||
| 55 | 679C > T | — | Gln 220 stop | EC(TNF) | D | NA | ||
| 56 | 679C > T | — | Gln 220 stop | EC(TNF) | D | D | ||
| 57 | 682C > T | — | Gln 221 stop | EC(TNF) | D | D | 31 | |
| 58 | 701G > T | — | Gly 227 Val | EC(TNF) | + | D | 31 | |
| 59 a,b | 713G > T | — | Leu 231 Ser | EC(TNF) | NA | NA | 31 | |
| 60 a,b | 724G > C | — | Ala 235 Pro | EC(TNF) | D | D | 31 | |
| 61 | 782C > T | — | Thr 254 Met | EC(TNF) | + | D | ||
| 62 | 782C > T | — | Thr 254 Met | EC(TNF) | + | D | 31,35 | |
| 63 | 782C > T | — | Thr 254 Met | EC(TNF) | + | D | 31 | |
| 64 a,b,c | 794T > C | — | Leu 258 Ser | EC(TNF) | + | D | 31 | |
| 65 a,b | 794T > C | — | Leu 258 Ser | EC(TNF) | + | D | 31 | |
| Deletions | ||||||||
| 66 | IVS4-1 g Del | Del 8 bp (431-8) | fs, stop 139 | EC(TNF) | NA | NA | 31 | |
| 67 | 445-50 Del 6 bp† | DelGAA AAA | Del 142 Glu, 143 Lys | EC(TNF) | + | D | ||
| 68 | 454-6 Del 3 bp† | Del TAC | Del 145 Tyr | EC(TNF) | + | D | ||
| 69 | 580 Del G† | — | fs, stop 190 | EC(TNF) | D | NA | ||
| 70 | 610-616 Del C† | — | fs, stop 241 | EC(TNF) | NA | NA | ||
| 71 | 699-701 Del 3 bp | Del AGG | Del 227 Gly | EC(TNF) | NA | NA | 36 | |
| Insertions | ||||||||
| 72 a,b | Ins 12 bp between IVS4-1 & nt 431 | Ins 12 bp between E4&E5 | Ins 4 aa between E4&E5 | EC(TNF) | D | D | ||
| 73 | Ins 9 bp between IVS4-1 & nt 431 | Ins 9 bp between E4&E5 | Ins 3 aa between E4&E5 | EC(TNF) | + | D | ||
| 74 | (445-451) insert A | — | fs, stop 164 | EC(TNF) | D | D | 31 | |
| 75 a,b | Duplicate CAGCC between 593C&599T | — | fs, stop 197 | EC(TNF) | D | D | 31 | |
| Deletions involving more than 2 exons | ||||||||
| 76 a,b | Del 33Kb including E1, E2, E3 | Del E1-E3 | Unstable protein | IC,TM,EC | D | D | 31 | |
| 77 | Del 56 Kb including E1-5 | Nondetectable cDNA | Unstable protein | IC,TM,EC | D | D | ||
. | . | . | . | . | Protein expression by flow cytometry . | . | . | |
|---|---|---|---|---|---|---|---|---|
| Family/Patient . | Genomic DNA mutation (nucleotide no.)* . | cDNA mutation (nucleotide no.)*if different from gDNA . | Predicted effect on protein . | Affected domain . | Anti-CD40L mAb . | CD40-Ig . | Reference‡ . | |
| Exon 1/Intron 1 | ||||||||
| Nonsense and missense mutations | ||||||||
| 1 | 52C > T | — | Arg 11 stop | IC | + | (+) | 31,35 | |
| 2 | 99T > G† | — | Tyr 26 stop | TM | D | D | ||
| 3 | 128T > G | — | Met 36 Arg | TM | NA | NA | 36 | |
| 4 | 175A > T | — | Lys 52 stop | EC | D | D | ||
| Splice site mutations | ||||||||
| 5 | IVS1 + 1 g > a† | Del 82 bp (nt 96-177) | fs, stop at 26 | TM | D | D | ||
| 6 | IVS1 + 1 g > t | Del 82 bp (nt 96-177) | fs, stop at 26 | TM | D | D | ||
| Del 10 bp (nt 168-177) | fs, stop at 50 | EC | ||||||
| Wild type cDNA | ||||||||
| 7 a,b,c | IVS1 + 1 g > t | Del 82 bp (nt 96-177) | fs, stop at 26 | EC | D | D | 31 | |
| Del 43 bp (nt 135-177) | fs, stop at 39 | EC | ||||||
| Del 10 bp (nt 168-177) | fs, stop at 50 | TM | ||||||
| Del 14 bp (nt 168-181) | fs, stop at 51 | TM | ||||||
| Wild type cDNA | ||||||||
| 8 | IVS1 + 1 g > t | Del 82 bp (nt 96-177) | fs, stop at 26 | TM | D | D | ||
| Wild type cDNA | ||||||||
| Exon2/Intron 2 | ||||||||
| Nonsense mutations | ||||||||
| 9 | 187G > T | — | Glu 56 stop | EC | D | D | 31 | |
| 10 | 229C > T | — | Gln 70 stop | EC | D | D | ||
| Deletions | ||||||||
| 11 | Del 9 bp aatagATAG | 178-81 Del ATAG | fs, stop at 65 | EC | NA | NA | ||
| 12 | Del 8 bp atagATAG | 178-81 Del ATAG | fs, stop at 65 | EC | NA | NA | 31,36 | |
| 13 | Del 8 bp atagATAG | 178-81 Del ATAG | fs, stop at 65 | EC | D | D | ||
| 14 | Del 4 bp ATAG | 178-81 Del ATAG | fs, stop at 65 | EC | NA | NA | ||
| 15 | Del 2 bp CA (229-30) | 229-30 Del CA | fs, stop at 84 | EC | NA | NA | ||
| Splice site mutations | ||||||||
| 16 a,b | IVS2 + 1 g > a | E2 skip | Inframe del 44 aa | EC | + | D | 31,36 | |
| Ins 19 bp (5′ part of 12) | fs, stop at 118 | |||||||
| 17 | IVS2 + 2 t > a | E2 skip | Inframe del 44 aa | EC | + | (+) | 31,35 | |
| Ins 19 bp (5′ part of 12) | fs, stop at 118 | |||||||
| Wild type cDNA | ||||||||
| Exon 3/Intron 3 | ||||||||
| Deletions | ||||||||
| 18 | 344-7 Del A† | A344-7 Del A | fs, stop at 127 | EC | D | D | ||
| Splice site mutations | ||||||||
| 19 | 367G > A | E3 skip (del 310-67) | fs, stop at 108 | EC | + | (+) | 31 | |
| Wild type cDNA | ||||||||
| 20 | 367G > C† | E3 skip (del 310-67) | fs, stop at 108 | EC | D | D | ||
| Lys 96 Asn | ||||||||
| 21 | IVS3 + 1 g > a | E3 skip (del 310-67) | fs, stop at 108 | EC | D | D | ||
| 22 | IVS3 + 1 g > a | E3 skip (del 310-67) | fs, stop at 108 | EC | D | D | ||
| 23 | IVS3 + 1 g > a | E3 skip (del 310-67) | fs, stop at 108 | EC | D | D | ||
| 24 | IVS3 + 1 g Del | E3 skip (del 310-67) | fs, stop at 108 | EC | D | D | ||
| 25 | IVS3 + 2 t > c | E3 skip (del 310-67) | fs, stop at 108 | EC | + | (+) | 31 | |
| Wild type cDNA | ||||||||
| 26 | IVS3 + 5 g > c | E3 skip (del 310-67) | fs, stop at 108 | EC | + | (+) | 31 | |
| Wild type cDNA | ||||||||
| 27 | IVS3-915a > t† | New splice site Ins 59 bp between E3&E4 | fs, stop at 127 | EC(TNF) | D | D | ||
| 28 a,b | IVS3-1 g > a | E4 skip (del 368-430) | Inframe del 21 aa | EC(TNF) | NA | NA | ||
| 29 | IVS3-1 g > c | E4 skip (del 368-430) | Inframe del 21 aa | EC(TNF) | D | NA | ||
| Exon 4/Intron 4 | ||||||||
| Missense mutations | ||||||||
| 30 | 405T > A | — | Ser 128 Arg | EC(TNF) | + | D | 31 | |
| 407A > G | — | Glu 129 Gly | ||||||
| Insertions | ||||||||
| 31 | 403-405 ins G | — | fs, stop at 129 | EC(TNF) | D | D | 31 | |
| 32 | 403-405 ins G | — | fs, stop at 129 | EC(TNF) | D | D | 31 | |
| 33 a,b,c | 411-413 ins A | — | fs, stop at 133 | EC(TNF) | NA | NA | 37 | |
| 34 | 417-422 ins A† | — | fs, stop at 142 | EC(TNF) | NA | NA | ||
| Splice site mutations | ||||||||
| 35 a,b,c,d,e | IVS4 + 1 g > c | E4 skip (del 368-430) | Inframe del 21 aa fs | EC(TNF) | + | D | 31 | |
| Ins 5′ part of IVS4 (23, 73, 152 bp) | ||||||||
| 36 | IVS4 + 1 g > c | E4 skip (del 368-430) | Inframe del 21 aa | EC(TNF) | + | D | 31 | |
| 37 | IVS4 + 1 g > c | E4 skip (del 368-430) | Inframe del 21 aa | EC(TNF) | NA | NA | ||
| 38 | IVS4 + 2 i > c | E4 skip (del 368-430) | Inframe del 21 aa | EC(TNF) | D | NA | ||
| Exon 5/Intron 5 | ||||||||
| Nonsense and missense mutations | ||||||||
| 39 | 436C > T† | — | Gln 139 stop | EC(TNF) | D | D | ||
| 40 | 440G > A | — | Trp 140 stop | EC(TNF) | D | D | 36 | |
| 41 | 456C > A | — | Thy 145 stop | EC(TNF) | D | NA | ||
| 42 | 461C > A | — | Thr 147 Asn | EC(TNF) | + | D | 31 | |
| 43 | 517C > T | — | Gln 166 stop | EC(TNF) | D | D | ||
| 44 a,b | 517C > T | — | Gln 166 stop | EC(TNF) | D | D | ||
| 45 a,b | 526T > G | — | Tyr 169 Asp | EC(TNF) | D | NA | ||
| 46 a,b | 530C > A | — | Tyr 170 Cys | EC(TNF) | D | D | 31 | |
| 47 | 541C > T† | — | Gln 174 stop | EC(TNF) | D | D | ||
| 48 | 577C > T | — | Gln 186 stop | EC(TNF) | D | D | 31 | |
| 49 | 577C > T | — | Gln 186 stop | EC(TNF) | NA | NA | ||
| 50 | 619A > T | — | Arg 200 stop | EC(TNF) | NA | NA | ||
| 51 | 619A > T | — | Arg 200 stop | EC(TNF) | D | D | ||
| 52 | 629G > T† | — | Arg 203 Ile | EC(TNF) | + | D | ||
| 53 | 675C > A | — | Cys 218 stop | EC(TNF) | NA | NA | ||
| 54 | 675C > A | — | Cys 218 stop | EC(TNF) | D | NA | ||
| 55 | 679C > T | — | Gln 220 stop | EC(TNF) | D | NA | ||
| 56 | 679C > T | — | Gln 220 stop | EC(TNF) | D | D | ||
| 57 | 682C > T | — | Gln 221 stop | EC(TNF) | D | D | 31 | |
| 58 | 701G > T | — | Gly 227 Val | EC(TNF) | + | D | 31 | |
| 59 a,b | 713G > T | — | Leu 231 Ser | EC(TNF) | NA | NA | 31 | |
| 60 a,b | 724G > C | — | Ala 235 Pro | EC(TNF) | D | D | 31 | |
| 61 | 782C > T | — | Thr 254 Met | EC(TNF) | + | D | ||
| 62 | 782C > T | — | Thr 254 Met | EC(TNF) | + | D | 31,35 | |
| 63 | 782C > T | — | Thr 254 Met | EC(TNF) | + | D | 31 | |
| 64 a,b,c | 794T > C | — | Leu 258 Ser | EC(TNF) | + | D | 31 | |
| 65 a,b | 794T > C | — | Leu 258 Ser | EC(TNF) | + | D | 31 | |
| Deletions | ||||||||
| 66 | IVS4-1 g Del | Del 8 bp (431-8) | fs, stop 139 | EC(TNF) | NA | NA | 31 | |
| 67 | 445-50 Del 6 bp† | DelGAA AAA | Del 142 Glu, 143 Lys | EC(TNF) | + | D | ||
| 68 | 454-6 Del 3 bp† | Del TAC | Del 145 Tyr | EC(TNF) | + | D | ||
| 69 | 580 Del G† | — | fs, stop 190 | EC(TNF) | D | NA | ||
| 70 | 610-616 Del C† | — | fs, stop 241 | EC(TNF) | NA | NA | ||
| 71 | 699-701 Del 3 bp | Del AGG | Del 227 Gly | EC(TNF) | NA | NA | 36 | |
| Insertions | ||||||||
| 72 a,b | Ins 12 bp between IVS4-1 & nt 431 | Ins 12 bp between E4&E5 | Ins 4 aa between E4&E5 | EC(TNF) | D | D | ||
| 73 | Ins 9 bp between IVS4-1 & nt 431 | Ins 9 bp between E4&E5 | Ins 3 aa between E4&E5 | EC(TNF) | + | D | ||
| 74 | (445-451) insert A | — | fs, stop 164 | EC(TNF) | D | D | 31 | |
| 75 a,b | Duplicate CAGCC between 593C&599T | — | fs, stop 197 | EC(TNF) | D | D | 31 | |
| Deletions involving more than 2 exons | ||||||||
| 76 a,b | Del 33Kb including E1, E2, E3 | Del E1-E3 | Unstable protein | IC,TM,EC | D | D | 31 | |
| 77 | Del 56 Kb including E1-5 | Nondetectable cDNA | Unstable protein | IC,TM,EC | D | D | ||
The small letters (a,b,c,d,e) indicate members from the same family.
Del indicates deletion; ins, insertion; fs, frameshift; E, exon; I, intron; IC, intracytoplasmic; TM, transmembrane; EC, extracellular; TNF, tumor necrosis factor homology domain; +, CD40L expression is normal; (+), CD40L detected, but decreased compared with normal; D, dramatically decreased or absent CD40L expression; NA, not available because of limited blood samples; —, no difference from gDNA.
Nucleotide number is based on the sequence data described by Hollenbaugh et al.57
Novel mutation, not yet reported.
References in which a specific patient was reported previously (see “References”).