title: Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway.
abstract: 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.
authors.affiliation: Genome Rearrangements and Cancer Laboratory, U462 INSERM, Laboratoire Central d'Hématologie and Institut Universitaire d'Hématologie, Hopital Saint-Louis, 1 Ave Claude Vellefaux, 75010 Paris, France. jsoulier@chu-stlouis.fr
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Thierry
authors.initials: T
authors.lastname: Leblanc
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
authors.forename: Hélène
authors.initials: H
authors.lastname: Dastot
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamura
authors.forename: Philippe
authors.initials: P
authors.lastname: Guardiola
authors.forename: Hélène
authors.initials: H
authors.lastname: Esperou
authors.forename: Christèle
authors.initials: C
authors.lastname: Ferry
authors.forename: Charlotte
authors.initials: C
authors.lastname: Jubert
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Feugeas
authors.forename: Annie
authors.initials: A
authors.lastname: Henri
authors.forename: Antoine
authors.initials: A
authors.lastname: Toubert
authors.forename: Gérard
authors.initials: G
authors.lastname: Socié
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.forename: François
authors.initials: F
authors.lastname: Sigaux
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
authors.forename: Eliane
authors.initials: E
authors.lastname: Gluckman
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002869:Chromosome Aberrations; D005199:Fanconi Anemia / Q000097:blood / Q000235:genetics*; D052236:Fanconi Anemia Complementation Group D2 Protein; D019398:Genes, BRCA1; D006801:Humans; D009030:Mosaicism; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D009687:Nuclear Proteins