title: Current knowledge on the pathophysiology of Fanconi anemia: from genes to phenotypes.
abstract: Fanconi anemia (FA) is an autosomal recessive disease characterized by congenital anomalies, bone marrow failure, and leukemia susceptibility. FA cells show chromosome instability and hypersensitivity to DNA cross-linking agents such as mitomycin C. Recent studies indicate that there are at least 8 genetically distinct FA groups (A, B, C, D1, D2, E, F, G). To date, 6 genes (for A, C, D2, E, F, and G) have been cloned. In this review, we describe the structures and functions of FA proteins. Increasing evidence indicates that the multiple FA proteins cooperate in a biochemical pathway and/or a multimer complex. FANCD2, a downstream component of the FA pathway, has recently been shown to be ubiquitinated in response to DNA damage and to translocate to nuclear foci containing BRCA1, a breast cancer susceptibility gene product, suggesting a role for this protein in DNA repair functions. We also describe 2 emerging issues: genotype-phenotype relationships and mosaicism. The FA pathway is likely to play a critical role as a caretaker of genomic integrity in hematopoietic stem cells. Clarifying the molecular basis of this disease may provide new insights into the pathogenesis of bone marrow failure syndromes and myeloid malignancies.
authors.affiliation: Division of Genetic Diagnosis, Institute of Medical Science, University of Tokyo, Japan. y-taka@ims.u-tokyo.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Yamashita
authors.forename: T
authors.initials: T
authors.lastname: Nakahata
mesh_terms: D000293:Adolescent; D000818:Animals; D019313:BRCA1 Protein / Q000502:physiology; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002877:Chromosomes, Human / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004249:DNA Damage; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D005199:Fanconi Anemia / Q000145:classification / Q000235:genetics / Q000503:physiopathology*; D052217:Fanconi Anemia Complementation Group A Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D052239:Fanconi Anemia Complementation Group E Protein; D052219:Fanconi Anemia Complementation Group F Protein; D052241:Fanconi Anemia Complementation Group G Protein; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D005544:Forecasting; D005808:Genes, Recessive; D005816:Genetic Complementation Test; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009030:Mosaicism / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000502:physiology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology
chemical_list: D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; C498471:FANCA protein, human; C499905:FANCD2 protein, human; C499907:FANCE protein, human; C499901:FANCF protein, human; C499909:FANCG protein, human; C120277:Fanca protein, mouse; C499904:Fancd2 protein, mouse; C499910:Fancg protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D052239:Fanconi Anemia Complementation Group E Protein; D052219:Fanconi Anemia Complementation Group F Protein; D052241:Fanconi Anemia Complementation Group G Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins; D016601:RNA-Binding Proteins