title: Molecular spectra of HPRT deletion mutations in circulating T-lymphocytes in Fanconi anemia patients.
abstract: The principal cellular feature of Fanconi anemia (FA), an inherited cancer prone disorder, is a high level of chromosomal breakage, amplified after treatment with crosslinking agents. Three of the eight genes involved in FA have been cloned: FANCA, FANCC and FANCG. However, their biological functions remain unknown. We previously observed an excessive production of deletions at the HPRT locus in FA lymphoblasts belonging to the relatively rare complementation group D(1) and an increased frequency of glycophorin A (GPA) variants in erythrocytes derived from FA patients (2). In thi study, we examined the molecular nature of 31 HPRT mutations formed in vivo in circulating T-lymphocytes isolated from 9 FA male patients. The results show that in all FA patients investigated the deletions are by far the most prevalent mutational event in contrast to age matched healthy donors, in which point mutations predominate. The complementation group in the FA patients examined in the present study has not yet been defined. However, knowing that mutations in the FANCA and FANCC gene are found to be involved in at least 70% of the FA patients, it can be expected that the excessive production of deletions is a general feature of the FA phenotype. In addition, the spectrum of HPRT deletions observed in FA patients differs from that of healthy children: there is a high frequency of 3'-terminal deletions and a strikingly low proportion of V(D)J mediated events. Based on previous findings, a decreased fidelity of coding V(D)J joint formation (3) and an inaccurate repair of specific DNA double strand breaks via Non-Homologous End Joining (4), we propose that FA genes play a role in the control of the fidelity of rejoining of specific DNA ends. Such a defect may explain several basic features of FA, such as chromosomal instability and deletion pronenness.
authors.affiliation: UMR218 du CNRS, Institut Curie-Recherche, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Laquerbe
authors.forename: M
authors.initials: M
authors.lastname: Sala-Trepat
authors.forename: C
authors.initials: C
authors.lastname: Vives
authors.forename: M
authors.initials: M
authors.lastname: Escarceller
authors.forename: D
authors.initials: D
authors.lastname: Papadopoulo
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D019457:Chromosome Breakage; D004254:DNA Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism; D005199:Fanconi Anemia / Q000235:genetics*; D015334:Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor / Q000235:genetics; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics* / Q000378:metabolism; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000502:physiology*; D045567:VDJ Recombinases
chemical_list: D007041:Hypoxanthine Phosphoribosyltransferase; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases