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 Blood, 1 February 2005, Vol. 105, No. 3, pp. 1329-1336.
Prepublished online as a Blood First Edition Paper on September 21, 2004; DOI 10.1182/blood-2004-05-1852.

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RED CELLS

Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway

Jean Soulier, Thierry Leblanc, Jérôme Larghero, Hélène Dastot, Akiko Shimamura, Philippe Guardiola, Hélène Esperou, Christèle Ferry, Charlotte Jubert, Jean-Paul Feugeas, Annie Henri, Antoine Toubert, Gérard Socié, André Baruchel, François Sigaux, Alan D. D'Andrea, and Eliane Gluckman

From the Laboratoire Central d'Hématologie et INSERM U462; Service d'Hématologie Pédiatrique; Unité de Thérapie Cellulaire; Service de Greffe de Moelle osseuse; Laboratoire de Thérapie Génique Hématologique; Laboratoire d'Immunogénétique Humaine; Institut Universitaire d'Hématologie (IUH); Hopital Saint-Louis, Paris, France; Department of Pediatric Oncology, Dana Farber Cancer Institute, Children's Hospital Boston; and Harvard Medical School, Boston, MA.

Fanconi anemia (FA) is characterized by congenital abnormalities, bone marrow failure, chromosome fragility, and cancer susceptibility. Eight FA-associated genes have been identified so far, the products of which function in the FA/BRCA pathway. A key event in the pathway is the monoubiquitination of the FANCD2 protein, which depends on a multiprotein FA core complex. In a number of patients, spontaneous genetic reversion can correct FA mutations, leading to somatic mosaicism. We analyzed the FA/BRCA pathway in 53 FA patients by FANCD2 immunoblots and chromosome breakage tests. Strikingly, FANCD2 monoubiquitination was detected in peripheral blood lymphocytes (PBLs) in 8 (15%) patients. FA reversion was further shown in these patients by comparison of primary fibro-blasts and PBLs. Reversion was associated with higher blood counts and clinical stability or improvement. Once constitutional FANCD2 patterns were determined, patients could be classified based on the level of FA/BRCA pathway disruption, as "FA core" (upstream inactivation; n = 47, 89%), FA-D2 (n = 4, 8%), and an unidentified downstream group (n = 2, 4%). FA-D2 and unidentified group patients were therefore relatively common, and they had more severe congenital phenotypes. These results show that specific analysis of the FA/BRCA pathway, combined with clinical and chromosome breakage data, allows a comprehensive characterization of FA patients.


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