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Natural gene therapy in monozygotic twins with Fanconi anemia

Mankad, Anuj, Taniguchi, Toshiyasu, Cox, Barbara, Akkari, Yassmine, Rathbun, R. Keaney, Lucas, Lora, Bagby, Grover, Olson, Susan, D'Andrea, Alan, Grompe, Markus·2006·Blood
DOI 10.1182/blood-2005-07-2638
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Abstract

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 (2555ΔT) 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.

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Metadata

Authors
Mankad, A., Taniguchi, T., Cox, B., Akkari, Y., Rathbun, R. K., Lucas, L., Bagby, G., Olson, S., D'Andrea, A., & Grompe, M.
Affiliations
From the Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR; the Dana Farber Cancer Institute, Harvard Medical School, Harvard University, Boston, MA; and the Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
Venue
Blood
Publisher
American Society of Hematology
Published
2006-04-15
Volume
107
Issue
8
Pages
3084-3090
ISSN
  • 0006-4971
  • 1528-0020
DOI
10.1182/blood-2005-07-2638
Cited by
70
References
1
Language
en

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CoChat. (2026). Citation check: Natural gene therapy in monozygotic twins with Fanconi anemia. https://app.cochat.ai/papers/10.1182/blood-2005-07-2638
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Mankad, A., Taniguchi, T., Cox, B., Akkari, Y., Rathbun, R. K., Lucas, L., Bagby, G., Olson, S., D'Andrea, A., & Grompe, M. (2006). Natural gene therapy in monozygotic twins with Fanconi anemia. Blood. https://doi.org/10.1182/blood-2005-07-2638