Mouse models of Fanconi anemia

Abstract

Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, thirteen complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability. Keywordsinterstrand crosslinks; gene targeting; mouse models; genome instability; tumors; stem cells Fanconi anemiaFanconi anemia is a rare autosomal recessive disease with a complex spectrum of symptoms including congenital skeletal and renal anomalies, growth retardation, pigmentation abnormalities, fertility defects, aplastic anemia, and increased risk of acute myeloid leukemia and epithelial tumors (see "Fanconi Anemia and its Diagnosis" Auerbach, this issue). Progressive bone marrow failure and late-developing myeloid malignancies account for 90% of mortality in FA patients. Bone marrow failure in FA children is attributed to the excessive apoptosis and subsequent failure of the hematopoietic stem cell compartment. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia (FA) pathway, a response mechanism to replicative stress (33). To date, thirteen complementation groups of Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptMutat Res. Author manuscript; available in PMC 2010 July 31. by clinical suspicion coupled with detecting an increased number of chromosomal aberrations in patient cells exposed to drugs that induce DNA interstrand crosslinks (ICLs). ICLs covalently tether both strands of the DNA helix together and therefore are an absolute block to the progression of a replication fork and a potent inducer of replication stress. Crosslinking agents induce replication-dependent double-strand breaks (DSBs) (54). These DSBs are subsequently repaired by homologous ...

The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA

“…The pattern of sterility among FA patients is also shared with FA gene knockouts in mice [17]. In fact, all FA mouse models to date exhibit the same fertility defect [18][19][20][21][22][23][24][25][26][27].…”

Les modèles animaux de l’anémie de Fanconi

“…Les revues de la littérature de Parmar et al [22] et de Bakker et al [23] en dressent une synthèse complète. Nous nous attarderons ici, à ne traiter que de la rationalisation des controverses actuelles.…”

Gene Therapy of Some Genetic Diseases by Transferring Normal Human Genomic DNA into Somatic Cells and Stem Cells from Patients

“…There are mouse models of Fanconi anemia available currently; FancA, FancC, FancG, FancD1, and FancD2 genes have been deleted or mutated in the mice (Parmar et al, 2009). …”