Nucleotide change | Amino acid change | Exon or Intron | Domain | Reported ex vivo %FOXP3+ cells | Molecular defect | References | Endocrinopathy | Enteropathy | Skin manifestations | Reported onset | Immunosuppression | Response to immunosuppression | HSCT | Outcome |
g.-6247_-4859del | NA | Exon-1 Intron-1 | Non-coding | Diminished | Accumulation of unspliced mRNA | Gavin et al, 200630; Torgerson et al, 200731; Moes et al, 201032 | N | Y | Y | <2 mth |
| Y | N | Treated patients stable at 6, 9 years |
c.1-7G>T | NA | Upstream of initiation codon | Non-coding | NA | New translation initiation site. Stop codon at 61aa | Myers et al, 200633 |
| Y | N | Birth | None | NA | N | Died at 54 days |
2T>C | M1T | Exon 1 | PRR | Diminished | Predicted abnormal reading frame | Gambineri et al, 200822 | T1D | Y | N | Birth | Steroids, tacrolimus | N | N | Died at 3 mth |
3G>A | M1I | Exon 1 | PRR | Diminished | Predicted abnormal reading frame | Bacchetta et al, 200634; Gambineri et al, 200822 |
| Y | Y | Birth | Steroids, CsA | N | Y | Stable at 5 years |
200G>T | Q70H | Exon 1 | PRR | NA | Predicted abnormal reading frame | Heltzer et al, 200735; Yong et al, 200829 | N | Y | Y | 1 mth | Sirolimus | Y | N | Stable at 8 years |
210+1G>A | NA | Intron 1 | Non-coding | NA | Predicted splicing defects | Tsuda et al, 201036; Bae et al, 201137 |
| Y | Y | 11 mth | Steroids | Y | N | Stable at 14 years |
210_210+1delGGinsAC | NA | Intron 1 | Non-coding | Diminished | Predicted splicing defects | Gavin et al, 200630 | T1D | Y | Y | 2 mth | Steroids, tacrolimus | Y | N | Stable at 5 mth |
210+2delTT | NA | Intron 1 | Non-coding | Diminished | Predicted splicing defects | Burroughs et al, 201038 | T1D | Y | N | 2 mth | Steroids, tacrolimus | N | Y | Stable at 4 years |
210+2T>G | NA | Intron 1 | Non-coding | NA | Predicted splicing defects | Gambineri et al, 200822 |
| Y | Y | Birth | Steroid, CsA, tacrolimus, IVIG | N | Y | Stable at 18 mth |
227delT | L76QfsX53 | Exon 2 | PRR | Diminished | Predicted stop codon at 128aa | Kobayashi et al, 200139; Fuchizawa et al, 200740; Rubio-Cabezas et al, 200941 | HTH | Y | N |
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303_304delTT | F102fsX103 | Exon 2 | PRR | NA | Predicted stop codon at 205aa | Moudgil et al, 200742; Rao et al, 200743 |
| Y | Y | Birth | Steroids, CsA, rituximab | N | Y | Stable at 2.5 years |
323C>T | T108M | Exon 3 | PRR | NA | Predicted to yield full length FOXP3 | De Benedetti et al, 200644 | N | Y | N | 14 mth | Steroids, azathioprine | Y | N | Stable at 7 years |
454+4A>G | NA | Intron 3 | Non-coding | NA |
| De Benedetti et al, 200644 | N | Y | Y | 11 days | Steroid, CsA, tacrolimus | Y | N | Stable at 22 years |
543C>T | S181S | Exon 5 | PRR | Elevated | Silent mutation. May affect RNA stability and splicing | Gambineri et al, 200822 | N | Y | N | Birth | Steroid, CsA, IVIG | N | N | Died at 5 mth |
560C>T | P187L | Exon 5 | PRR | Normal | Full length protein | Moes et al, 201032 | N | Y | Y | Birth | Tacrolimus | N | Y | Died due to severe GVHD at 8 years |
725T>C | L242P | Exon 6 | LZ | Reduced | Missense mutation. Predicted to yield full length FOXP3 | Gambineri et al, 200822; Passerini et al, 201145 | N | Y | Y | 4 mth | Steroid, CsA, tacrolimus | N | Y | Stable at 14 years |
736-1G>A | ΔL246_V272 | Intron 6 | LZ | NA | Splicing defect. Exon 7 skipping | Halabi-Tawil et al, 200920 |
| Y | Y | NA | NA | NA | NA | NA |
748_750delAAG | ΔLys250 | Exon 7 | LZ | NA | Disrupts FOXP3 oligomerisation | Wildin et al, 200246; Li et al, 200747 | T1D | Y | N | 2 mth | Steroid, CsA, tacrolimus | N | Y | Died at 9 years due to BMT complications |
750_752delGGA | ΔGlu251 | Exon 7 | LZ | Reduced | Disrupts FOXP3 oligomerisation | Gavin et al, 200630; Moes et al, 201032 |
| Y | Y |
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816+2del | NA | Intron 7 | Non-coding | NA | Predicted splicing defect | Passerini et al, 201145 | N | Y | Y | 5 mth | Yes. Drugs not specified | Y | N | Stable at 27 years |
816+4A>G | NA | Intron 7 | Non-coding | NA | Predicted skipping of exon 7 | Harbuz et al, 201048 | N | Y | Y | 2 mth | Steroids | N | N | Died at 3 years |
816+5G>A | NA | Intron 7 | Non-coding | NA | Predicted splicing defect | Gambineri et al, 200822 | T1D | Y | Y | Birth | Steroids, Azathioprine | N | N | Died at 9 mth |
816+7G>C | NA | Intron 7 | LZ | Reduced | Splicing defect. Exon 7 skipping, affecting the leucine-zipper domain | Harbuz et al, 201048; Burroughs et al, 201038 |
| Y | Y |
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817-1G>A | NA | Intron 7 | Non-coding | NA | Predicted skipping of exon 7 | Heltzer et al, 200735 | T1D | Y | Y | Birth | Tacrolimus | N | N | Died at 79 days |
817G>T | A273S | Exon 8 | LZ-FKH loop | NA | Predicted impact on RUNX1 binding | Tsuda et al, 201036 | HTH | Y | Y | NA | NA | NA | NA | Alive at 6 years |
968+4A>G | NA | Intron 8 | Non-coding | NA | Skipping of exon 8. Predicted impact on RUNX1 binding | Gambineri et al, 200822 | T1D | Y | Y | Birth | Steroids, Tacrolimus, azathioprine | Y | N | Stable at 4 years |
970T>C, 972C>T | F324L | Exon 9 | LZ-FKH loop | Normal | Predicted impact on RUNX1 binding | Bacchetta et al, 200634; Gambineri et al, 200822 | N | Y | Y | 4 mth | No | NA | N | Stable at 7 years |
1010G>A | R337Q | Exon 9 | FKH boundary | NA | Missense mutation. Likely to affect DNA binding affinity | Rubio-Cabezas et al, 200941 | T1D | Y | N | 1 mth | NA | NA | N | Died at 13 mth |
1015C>G | P339A | Exon 9 | FKH | Reduced | Missense mutation. Predicted to yield full length FOXP3 | Gambineri et al, 200822; Rubio-Cabezas et al, 200941; Moes et al, 201032 |
| Y | Y |
| Steroids, tacrolimus, azathioprine, sirolimus | N | N |
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1040G>A | R347H | Exon 9 | FKH | Reduced | Effect on nuclear targeting. Abrogation of IL-2 repression | Gambineri et al, 2008; McMurchy et al, 2010; Passerini et al, 2011 | T1D | Y | Y |
| Steroids, CsA | Y | N | Stable at 10, 19 years |
1040G>A | R347H | Exon 9 | FKH | Reduced | Effect on nuclear targeting. Abrogation of IL-2 repression | Gambineri et al, 200822; McMurchy et al, 201049; Passerini et al, 201145 | T1D | Y | Y |
| Steroids, CsA | Y | N | Stable at 10, 19 years |
1044+4A>G | E323GfsX14 | Intron 9 | FKH | NA | Skipping of exon 9. Abnormal FKH domain | Chatila et al, 200050 | T1D | Y | Y | Infancy | NA | NA | NA | NA |
1045-3C>G | NA | Intron 9 | Non-coding | Reduced | Retention of intron 9. Abnormal FKH domain | Costa-Carvalho et al, 200851 |
| Y | Y | Birth | Steroids | N | N | Died at 10 mth |
1061delC | Frameshift | Exon 10 | FKH | NA | Deletion and frameshift. Premature stop codon. Truncated FKH domain | Heltzer et al, 200735; Yong et al, 200829 | N | Y | Y | 2 years |
| Y | N |
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1080_1081insA | N361KfsX2 | Exon 10 | FKH | Diminished | Truncated FKH domain | An Yf et al, 201127 | T1D | Y | Y | 20 days | No | NA | N | Died at 1 mth |
1087A>G | I363V | Exon 10 | FKH | NA | Missense mutation. Predicted to yield full length FOXP3 | Kobayashi et al, 200139 |
| Y | N | Early infancy | No | NA | N | Died at 3 years |
1100T>G | F367C | Exon 10 | FKH | Normal | Full length FOXP3 with abnormal FKH domain | Patey-Mariaud de Serre et al, 200918 | T1D | Y | N | 15 mth | NA | NA | NA | NA |
1101C>G, c.1099T>C | F367L | Exon 10 | FKH | NA | Full length FOXP3 with abnormal FKH domain | Suzuki et al, 200753; Halabi-Tawil et al, 200920 |
| Y | Y | 8 days | No | NA | N | Died at 4 mth |
1110G>A | M370I | Exon 10 | FKH | Normal | Full length FOXP3 with abnormal FKH domain | An Yf et al, 201127 | N | Y | Y | 14 days | No | NA | N | Died at 11 mth |
1113T>G | F371C | Exon 10 | FKH | Normal | Full length FOXP3 with abnormal FKH domain | Wildin et al, 200110; Baud et al, 200154; Patey-Mariaud de Serre et al, 200918 | T1D | Y | Y | 4 wk | Steroids | N | Y | Stable at 2 years |
1117T>G | F373V | Exon 10 | FKH | Reduced | Full length FOXP3 with abnormal FKH domain | Tanaka et al, 200455; Tanaka et al, 200556; Fuchizawa et al, 200740 | N | Y | N | 2 mth | Steroids, CsA, IVIG | Y | N | Stable at 3.2 years |
1117_1118delTTinsGC | F373A | Exon 10 | FKH | Normal | Full length FOXP3 with abnormal FKH domain | Bacchetta et al, 200634; Gambineri et al, 200822; McMurchy et al, 201049; Passerini et al, 201145 | T1D | Y | Y | 2 wk | MMF | N | Y | Stable at 7 years |
1121 T>G | F374C | Exon 10 | FKH | Reduced | Full length FOXP3 with abnormal FKH domain | Gambineri et al, 200822; Moes et al, 201032 |
| Y | Y | Birth |
| N | N |
|
1139C>T | T380I | Exon 10 | FKH | NA | Full length FOXP3 with abnormal FKH domain | Zhan et al, 200857 | N | Y | N | 4 mth | Steroids, tacrolimus, azathioprine | N | Y | Stable at 3 years |
1150G>A | A384T | Exon 11 | FKH | Reduced | Full length FOXP3 with abnormal FKH domain | Wildin et al, 200110; Nieves et al, 200419; Gambineri et al, 200822; d'Hennezel et al, 200928 |
| Y | Y | Birth |
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| N |
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1157G>A | R386H | Exon 11 | FKH | NA | Full length FOXP3 with abnormal FKH domain | Tsuda et al, 201036 | N | Y | N | Early infancy | NA | NA | NA | Alive at 4 mth |
1169G>A | S390N | Exon 11 | FKH | NA | Full length FOXP3 with abnormal FKH domain | Myers et al, 200633; Tsuda et al, 201036 | T1D | Y | Y | Day 4 |
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| N |
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1190G>A | R397Q | Exon 11 | FKH | NA | Full length FOXP3 with abnormal FKH domain | Tsuda et al, 201036 | T1D | Y | Y | NA | NA | NA | NA | Alive at 4 years |
1189C>T | R397W | Exon 11 | FKH | NA | Full length FOXP3 with abnormal FKH domain. Impaired DNA binding | Levy-Lahad et al, 200158; Lopes et al, 200659 |
| Y | N | Birth |
| N | N |
|
1222G>A | V408M | Exon 11 | FKH | NA | Full length FOXP3 with misfolded FKH domain | Rubio-Cabezas et al, 200941 |
| Y | N | 3.5 mth | Steroids | Y | N | Stable at 12 years |
1226A>G | D409G | Exon 11 | FKH | NA | Full length FOXP3 with abnormal FKH domain | Rao et al, 200743 | T1D | Y | N | Early infancy | Steroids, tacrolimus, rituximab, alemtuzumab | N | Y | Stable at 6 mth |
1271 G>A | C424Y | Exon 11 | C-terminal | NA | Missense mutation downstream of FKH domain | Rao et al, 200743; Burroughs et al, 200760 |
| Y | Y | NA | Steroids, tacrolimus, MMF | N | Y | Stable at 4 years |
1290_1309delinsTGG | G430fsX22 | Exon 11 | Stop codon | NA | Deletion/insertion mutation yielding an elongated amino acid sequence | Peake et al, 199661; Wildin et al, 200110 | T1D | Y | Y | 6 wk | No | NA | N | Died at 10 mth |
1293_1294delCT | ter432TfsX26 | Exon 11 | Stop codon | NA | Frameshift/deletion mutation yielding elongated amino acid sequence | Bennett et al, 20013; Wildin et al, 200246 | NA | NA | NA | NA | NA | NA | NA | NA |
c.*876A>G (AAUAAA→AAUGAA) | NA | PolyA sequence | PolyA sequence | No FOXP3 mRNA | Polyadenylation defect resulting in unstable FOXP3 mRNA | Bennett et al, 200162. Tsuda et al, 201036 | N | Y | Y | Birth | NA | NA | NA | NA |
AAUAAA→AAUAAG | NA | PolyA sequence | PolyA sequence | Diminished | Polyadenylation defect resulting in unstable FOXP3 mRNA | Dorsey et al, 200963 | T1D | Y | Y | Birth | Steroids, sirolimus | N | Y | Stable at 8.5 mth |
↵* Not necessarily in combination.
FKH, forkhead domain; HSCT, haematopoietic stem cell transfer; HTH, hypothyroidism; PRR, proline-rich region; T1D, type 1 diabetes mth, month; wk, week; N, no; Y, yes; CsA, Cyclosporin A; IVIG, intra-veinous Immunoglobulin; NA, not available; aa, amino acid; BMT, bone marrow transplantation; LZ, leucin zipper; Δ, deletion; fs, frameshift; mRNA, messenger RNA; PolyA, Polyadenylation sequence; g., genomic sequence; c., coding sequence; del, deletion; ins, insertion.