Table 3

DNA alterations in patients with reversion of genotype +/− phenotype

DiseaseNucleotide number normal→mutant→reverted aminoacidRevertant cellsIn vitro/in vivoType of reversionGenotypeReference
Changes in bold cannot be explained by currently accepted non-random mechanisms for site specific reversion.
Single nt, site specific reversion to normal of a single nucleotide; LCL, lymphoid cell lines.
*Parents not available for study and therefore mosaicism could be somatic mosaicism due to de novo mutation during a relatively late stage of embryogenesis with a selective advantage for original heterozygous normal cells. Conversely, reversion cannot be excluded.
†Note possible effect of PEG ADA in observed loss of revertant cells: reduction of toxic metabolites and eliminatiion of selective advantage for normal cells.
‡The original t→a mutation results in a cryptic splice site and inclusion of 13 bp of intron into mRNA); a “second site” deletion of 11 bp that includes the cryptic splice site results in reversion to normal splicing
§Most reversions in Bloom syndrome are due to intragenic recombination, probably as a result of the basic pathology of the disease gene and are not included in this table.
Bp of intron results in use of normal splice site.
¶In FANC C, 332delG is now called 67delG.
**6bp deletion associated with nucleotide change, resulting in use of original splice site.
In vivo is also used to designate that cells and or tissues were tested without culturing in vitro.
Tyrosinaaemia 192 CAG→CAT→CAG 64 Gln→His→Gln Liver noduleYesSingle ntHomozygous 17
Abnormal splice 1009GGC→AGC→GGC 337 Gly→Ser→Gly Liver noduleYesSingle ntHomozygous 17
IVS12+5 G→A→GLiver noduleYesSingle ntHeterozygous 17
IVS12+5 G→A→GLiver noduleYesSingle ntHeterozygous 17
IVS12+5 G→A→G Liver noduleNA/yesSingle ntHomozygous 18
836 CAG→CGG→CAG 279 Gln→Arg→GlnLiver noduleYes/yesSingle nt ?CpG hotspotHeterozygous 19
ADA-SCID (severe combined immuno-deficiency)IVS1 +1g→c→g*B cells/PBLYes/yesSingle ntHeterozygous22*
467 CGC→CAC→CGC 156 Arg→His→ArgB cells/ PBLYes/yesSingle ntHeterozygous 23
355 CAG→TAG→CAG 119 Gln→Stop→GlnT cellsYes/yesSingle ntHeterozygous 24
704 CGG→CAG→CGG 235 Arg→Gln→ArgT cellsYes/no†Single ntHeterozygous 24
IVS11-15t→a‡ (cryptic splice)→del −4 to −14 IVS11‡B cells/PBLYes/yesSecond site mutationHomozygous 25
X linked SCID 343 TGT→CGT→TGT 115 Cys→Arg→Cys T cells (sorted)Yes/yesSingle nt ?hot spot CpGHemizygous 32
Wiskott-Aldrich (X linked) 354 TAC→TGC→TAC 107 Tyr→Cys→Tyr T cellsYes/yesSingle ntHemizygous 40
[ACGAGG]→434ins6 bp/del 6 bpT cellsYes/yesDel repeatHemizygous 41
1131G→del 1131G→[del G+ins1100A]LymphocytesNT/yesSecond site mutationHemizygous 42
Bloom Syndrome§1544 9As→10As (insA)→9As (delA)Fibroblast, PBLYes/yes?SlippageHomozygous 44
2702 TGT→TAT→TGT 901 Cys→Tyr→Cys LCLYes/yesSingle nt (father NT)Homozygous 44
Epidermolysis bullosa
COL 17A11706A→del 1706A→ins1706ASkin cells onlyYes/yesMitotic gene conversionHeterozygous 45
COL 17A14003TC→delTC→delTC+ins4080GGSkin (laser dissected)?Yes/yesSecond site del/insHomozygous 46
Keratin 14IVS1 −2a→cSkinYes/yes**PseudogeneHomozygous 47
Fanconi anaemia
FANC A1615G→1615delG→1615delg1637delA1641delTBlood cells, LCLsYes/?Second site deletionsHomozygous 50
3559→3559insG→3559insG3580insCGCTGBlood cells, LCLYes/?Second site insertionsHomozygous 50
2815 Ins19 bp→del ins 19BPHaematopoietic cells (?stem cell)Yes/?yesIns/del repeat hot spotHeterozygous 53
856 CAG→TAG→CAG 256 Gln→Stop→GlnBlood cells, LCLYes/?yesSingle ntHeterozygous 51
862 GAG→TAG→GAG288 Glu→Stop→GluBlood cells, LCLYes/?yesSingle ntHeterozygous 51
971 CTG→CGG→CTG324 Leu→Arg→LeuBlood cells, LCLYes/yesSingle ntHeterozygous 51
2852 CGG→CAG→CGG 951 Arg→Gln→ArgBlood cells, LCLYes/?yesSingle nt & repeat ?slippageHeterozygous 51
FANC C322delG¶/1806insA→ wild-type with absence of both mutations in a cloneBlood cells LCLIntragenic recombinationHeterozygous 50
322G→→322delG¶→322GBlood cells LCLYes/yesNot intragenic recombinationHeterozygous50
Sib of above: same changes
1749 CTT→CGT→TGT 496 Leu→Arg→CysBlood cells LCLYesSecond site ?CpG hot spot 52
67delG ¶Intragenic recombinationHeterozygous 51