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Blood, 15 April 2006, Vol. 107, No. 8, pp. 3084-3090.
Prepublished online as a Blood First Edition Paper on January 5, 2006; DOI 10.1182/blood-2005-07-2638.
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Submitted July 5, 2005
Accepted November 28, 2005
Natural gene therapy in monozygotic twins with Fanconi anemia
Anuj Mankad*, Toshiyasu Taniguchi, Barbara Cox, Yassmine Akkari, R K Rathbun, Lora Lucas, Grover Bagby, Susan Olson, Alan D'Andrea, and Markus Grompe
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
Dana Farber Cancer Institute, Harvard Medical School, Harvard University, Boston, MA, USA; Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Dana Farber Cancer Institute, Harvard Medical School, Harvard University, Boston, MA, USA
* Corresponding author; email: mankada{at}ohsu.edu.
Monozygotic twin sisters, with non-hematological 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 (2555 T) 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 hematopoietic symptoms for over two 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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