Mutations of the CD40L Gene and Immunostaining Types in Patients With XHIM
| Family* . | Patient . | Age† . | cDNA Mutation‡ (nucleotide no.) . | Expected Protein Alteration (amino acid no.) . | Genomic DNA Mutation‡ (nucleotide no.) . | Location . | Staining Type§ . | References∥ . |
|---|---|---|---|---|---|---|---|---|
| Missense and nonsense mutations | ||||||||
| 1 (W) | CD | 18 | 405T → A + 407A → G | S128R + E129G | 405T → A + 407A → G | Exon 4 | 3 | 7, 26 |
| 2 (W) | LB | 11 | 461C → A | T147N | 461C → A | Exon 5 | 2 | 15 |
| 3 (W) | JC/SC | 16/7 | 530A → G | Y170C | 530A → G | Exon 5 | 4 | 15 |
| 4 (W) | CF | (29) | 701G → T | G227V | 701G → T | Exon 5 | 3 | 11, 29 |
| 5 (A) | TY/AY | 12/5 | 713T → C | L231S | 713T → C | Exon 5 | ND | 25 |
| 6 (W) | JW | (26) | 724G → C | A235P | 724G → C | Exon 5 | 4 | 7, 26 |
| 7 (W) | TA | 18 | 782C → T | T254M | 782C → T | Exon 5 | 2 | 15, 25,40 |
| 8 (A) | IN | 24 | 782C → T | T254M | 782C → T | Exon 5 | 2 | 25, 40, 59 |
| 9 (W) | YL/JoB/JaB | 21/3/1 | 794T → C | L258S | 794T → C | Exon 5 | 3 | 15 |
| 10 (W) | DA/PA | 28/26 | 794T → C | L258S | 794T → C | Exon 5 | 3 | 15 |
| 11 (W) | DJ | 18 | 52C → T | R11X | 52C → T | Exon 1 | 1 | 60 |
| 12 (A) | NC | 21 | 187G → T | E56X | 187G → T | Exon 2 | 4 | |
| 13 (A) | KyS/KiS | (6)/5 | 440G → A | W140X | 440G → A | Exon 5 | 4 | 8, 13, 25, 27, 28 |
| 14 (W) | MB | 4 | 577C → T | Q186X | 577C → T | Exon 5 | 4 | |
| 15 (W) | WB | 11 | 682C → T | Q221X | 682C → T | Exon 5 | 4 | 29, 38 |
| Splice site mutations | ||||||||
| 16 (W) | DS/GS/DB | (40)/(24)/15 | del 82 bp (nt 96-177) | pt at aa 25 | nt 177 + 1g → t | Intron 1 | 4 | 3, 7, 11, 29 |
| del 43 bp (nt 135-177) | pt at aa 38 | |||||||
| del 10 bp (nt 168-177) | pt at aa 49 | |||||||
| del 14 bp (nt 168-181) | pt at aa 50 | |||||||
| Wild-type mRNA¶ | Wild type CD40L | |||||||
| 17 (A) | YA/TaA | 24/17 | del 132 bp (nt 178-309) (exon 2 skipping) | In-frame del 44 aa | nt 309 + 1g → a | Intron 2 | 2 | 25 |
| ins 19bp (5′ part of intron 2) | pt at aa 117 | |||||||
| 18 (W) | PS | 20 | Same as family 17 | Same as family 17 | nt 309 + 2t → a | Intron 2 | 1 | |
| 19 (W) | AM | 13 | del 58 bp (nt 310-367) (exon 3 skipping) | pt at aa 107 | nt 367G → A | Exon 3 | 1 | |
| Wild-type mRNA¶ | G116S | |||||||
| 20 (B) | MS | 1 | del 58 bp (nt 310-367) (exon 3 skipping) | pt at aa 107 | nt 367 + 2t → c | Intron 3 | 1 | |
| Wild-type mRNA¶ | Wild-type CD40L | |||||||
| 21 (W) | JE | 6 | Same as family 20¶ | Same as family 20 | nt 367 + 5g → a | Intron 3 | 1 | |
| 22 (W) | JoC/SeC/MC/ RoC/RiC | (0.7)/22/ (17)/15/11 | del 63 bp (nt 368-430) (exon 4 skipping) | In-frame del 21 aa | nt 430 + 1g → c | Intron 4 | 3 | 3, 25, 26, 29 |
| ins 23 bp, 73 bp, or 152 bp (5′ part of intron 4) | pt at aa 121 | |||||||
| 23 (A) | RA | 2 | Same as family 22 | Same as family 22 | nt 430 + 1g → a | Intron 4 | 3 | 10, 25 |
| 24 (A) | KA | (19) | del 8bp (nt 431-438) | pt to aa 138 | del nt 431-1g | Intron 4 | ND | 25 |
| Deletions and insertions | ||||||||
| 25 (A) | SU | 9 | del ATAG (nt 178-181) | pt at aa 64 | del ATAG between nt 178-5a and nt 182A | Intron 2exon 3 | ND | 25,39 |
| 26 (A) | JiB/TP | 16/6 | No mRNA | No protein | del more than 10 kb | Upstream of exon 4 | 5 | |
| 27 (W) | MR | 2 | ins G between nt 403A and nt 405T | pt at aa 128 | ins G between nt 403A and nt 405T | Exon 4 | 4 | 29 |
| 28 (W) | JG | 9 | Same as family 27 | Same as family 27 | Same as family 27 | Exon 4 | 4 | 29 |
| 29 (B) | DG | 15 | ins A between nt 445G and nt 451G | pt at aa 163 | ins A between nt 445G and nt 451G | Exon 5 | 4 | |
| 30 (W) | JJ/CJ | (23)/(24) | ins CAGCC between nt 593C and nt 599T | pt at aa 196 | ins CAGCC between nt 593C and nt 599T | Exon 5 | 4 | 24 |
| Family* . | Patient . | Age† . | cDNA Mutation‡ (nucleotide no.) . | Expected Protein Alteration (amino acid no.) . | Genomic DNA Mutation‡ (nucleotide no.) . | Location . | Staining Type§ . | References∥ . |
|---|---|---|---|---|---|---|---|---|
| Missense and nonsense mutations | ||||||||
| 1 (W) | CD | 18 | 405T → A + 407A → G | S128R + E129G | 405T → A + 407A → G | Exon 4 | 3 | 7, 26 |
| 2 (W) | LB | 11 | 461C → A | T147N | 461C → A | Exon 5 | 2 | 15 |
| 3 (W) | JC/SC | 16/7 | 530A → G | Y170C | 530A → G | Exon 5 | 4 | 15 |
| 4 (W) | CF | (29) | 701G → T | G227V | 701G → T | Exon 5 | 3 | 11, 29 |
| 5 (A) | TY/AY | 12/5 | 713T → C | L231S | 713T → C | Exon 5 | ND | 25 |
| 6 (W) | JW | (26) | 724G → C | A235P | 724G → C | Exon 5 | 4 | 7, 26 |
| 7 (W) | TA | 18 | 782C → T | T254M | 782C → T | Exon 5 | 2 | 15, 25,40 |
| 8 (A) | IN | 24 | 782C → T | T254M | 782C → T | Exon 5 | 2 | 25, 40, 59 |
| 9 (W) | YL/JoB/JaB | 21/3/1 | 794T → C | L258S | 794T → C | Exon 5 | 3 | 15 |
| 10 (W) | DA/PA | 28/26 | 794T → C | L258S | 794T → C | Exon 5 | 3 | 15 |
| 11 (W) | DJ | 18 | 52C → T | R11X | 52C → T | Exon 1 | 1 | 60 |
| 12 (A) | NC | 21 | 187G → T | E56X | 187G → T | Exon 2 | 4 | |
| 13 (A) | KyS/KiS | (6)/5 | 440G → A | W140X | 440G → A | Exon 5 | 4 | 8, 13, 25, 27, 28 |
| 14 (W) | MB | 4 | 577C → T | Q186X | 577C → T | Exon 5 | 4 | |
| 15 (W) | WB | 11 | 682C → T | Q221X | 682C → T | Exon 5 | 4 | 29, 38 |
| Splice site mutations | ||||||||
| 16 (W) | DS/GS/DB | (40)/(24)/15 | del 82 bp (nt 96-177) | pt at aa 25 | nt 177 + 1g → t | Intron 1 | 4 | 3, 7, 11, 29 |
| del 43 bp (nt 135-177) | pt at aa 38 | |||||||
| del 10 bp (nt 168-177) | pt at aa 49 | |||||||
| del 14 bp (nt 168-181) | pt at aa 50 | |||||||
| Wild-type mRNA¶ | Wild type CD40L | |||||||
| 17 (A) | YA/TaA | 24/17 | del 132 bp (nt 178-309) (exon 2 skipping) | In-frame del 44 aa | nt 309 + 1g → a | Intron 2 | 2 | 25 |
| ins 19bp (5′ part of intron 2) | pt at aa 117 | |||||||
| 18 (W) | PS | 20 | Same as family 17 | Same as family 17 | nt 309 + 2t → a | Intron 2 | 1 | |
| 19 (W) | AM | 13 | del 58 bp (nt 310-367) (exon 3 skipping) | pt at aa 107 | nt 367G → A | Exon 3 | 1 | |
| Wild-type mRNA¶ | G116S | |||||||
| 20 (B) | MS | 1 | del 58 bp (nt 310-367) (exon 3 skipping) | pt at aa 107 | nt 367 + 2t → c | Intron 3 | 1 | |
| Wild-type mRNA¶ | Wild-type CD40L | |||||||
| 21 (W) | JE | 6 | Same as family 20¶ | Same as family 20 | nt 367 + 5g → a | Intron 3 | 1 | |
| 22 (W) | JoC/SeC/MC/ RoC/RiC | (0.7)/22/ (17)/15/11 | del 63 bp (nt 368-430) (exon 4 skipping) | In-frame del 21 aa | nt 430 + 1g → c | Intron 4 | 3 | 3, 25, 26, 29 |
| ins 23 bp, 73 bp, or 152 bp (5′ part of intron 4) | pt at aa 121 | |||||||
| 23 (A) | RA | 2 | Same as family 22 | Same as family 22 | nt 430 + 1g → a | Intron 4 | 3 | 10, 25 |
| 24 (A) | KA | (19) | del 8bp (nt 431-438) | pt to aa 138 | del nt 431-1g | Intron 4 | ND | 25 |
| Deletions and insertions | ||||||||
| 25 (A) | SU | 9 | del ATAG (nt 178-181) | pt at aa 64 | del ATAG between nt 178-5a and nt 182A | Intron 2exon 3 | ND | 25,39 |
| 26 (A) | JiB/TP | 16/6 | No mRNA | No protein | del more than 10 kb | Upstream of exon 4 | 5 | |
| 27 (W) | MR | 2 | ins G between nt 403A and nt 405T | pt at aa 128 | ins G between nt 403A and nt 405T | Exon 4 | 4 | 29 |
| 28 (W) | JG | 9 | Same as family 27 | Same as family 27 | Same as family 27 | Exon 4 | 4 | 29 |
| 29 (B) | DG | 15 | ins A between nt 445G and nt 451G | pt at aa 163 | ins A between nt 445G and nt 451G | Exon 5 | 4 | |
| 30 (W) | JJ/CJ | (23)/(24) | ins CAGCC between nt 593C and nt 599T | pt at aa 196 | ins CAGCC between nt 593C and nt 599T | Exon 5 | 4 | 24 |
Polymorphism, nt 169T → C (L50L) described by Aruffo et al,7 was found in families 1, 6, 9, 12, 19, and 21.
Abbreviations: nt, nucleotide number; del, deletion; ins, insertion; pt, premature termination; aa, amino acid; ND, not done.
*Race: W, white; B, African-American; A, Asian.
†Age in years as of September 1997; ( ), age at death.
‡Nucleotide number is based on the sequence data described by Hollenbaugh et al.4
§Immunostaining pattern (types 1-5) of activated T-cell lines or CD4+ T-cell clones using one pAb, four MoAbs, and bCD40-Ig. See details in Table 2 and Fig 2.
∥References that report the patient listed with or without detailing the mutation. Reference numbers that are underlined indicate those describing the same mutations found by others in unrelated subjects.
¶Wild-type mRNA transcripts (or normally spliced mRNA transcripts in the case of family 19) were identified by RT-PCR and subsequent cloning.