Natural gene therapy in monozygotic twins with Fanconi anemia.
Monozygotic twin sisters, with nonhematologic symptoms of Fanconi anemia (FA), were discovered to be somatic mosaics for mutations in the FANCA gene. Skin fibroblasts, but not lymphocytes or committed hematopoietic progenitors, were sensitive to DNA cross-linking agents. Molecular analysis revealed, in skin cells of both twins, a frameshift causing deletion in exon 27 (2555deltaT) and an exon 28 missense mutation (2670G>A/R880Q). The latter resulted in primarily cytoplasmic expression and reduced function of the mutant FANCA (R880Q) protein. Surprisingly, the same acquired exon 30 missense change (2927G>A/E966K) was detected in the hematopoietic cells of both sisters, but not in their fibroblasts, nor in either parent. This compensatory mutation existed in cis with the maternal exon 28 mutation, and it restored function and nuclear localization of the resulting protein. Both sisters have been free of hematologic symptoms for more than 2 decades, suggesting that this de novo mutation occurred prenatally in a single hematopoietic stem cell (HSC) in one twin and that descendants of this functionally corrected HSC, via intra-uterine circulation, repopulated the blood lineages of both sisters. This finding suggests that treating FA patients with gene therapy might require transduction of only a few hematopoietic stem cells.
Mankad
Anuj
A
Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
Taniguchi
Toshiyasu
T
Cox
Barbara
B
Akkari
Yassmine
Y
Rathbun
R Keaney
RK
Lucas
Lora
L
Bagby
Grover
G
Olson
Susan
S
D'Andrea
Alan
A
Grompe
Markus
M
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D005091:Exons / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation; D005786:Gene Expression Regulation / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008431:Maternal-Fetal Exchange; D009030:Mosaicism; D020125:Mutation, Missense; D011247:Pregnancy; D012867:Skin / Q000378:metabolism / Q000473:pathology
D003432:Cross-Linking Reagents; C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein