title: Biallelic inactivation of REV7 is associated with Fanconi anemia.
abstract: Fanconi anemia (FA) is a recessive genetic disease characterized by congenital abnormalities, chromosome instability, progressive bone marrow failure (BMF), and a strong predisposition to cancer. Twenty FA genes have been identified, and the FANC proteins they encode cooperate in a common pathway that regulates DNA crosslink repair and replication fork stability. We identified a child with severe BMF who harbored biallelic inactivating mutations of the translesion DNA synthesis (TLS) gene REV7 (also known as MAD2L2), which encodes the mutant REV7 protein REV7-V85E. Patient-derived cells demonstrated an extended FA phenotype, which included increased chromosome breaks and G2/M accumulation upon exposure to DNA crosslinking agents, γH2AX and 53BP1 foci accumulation, and enhanced p53/p21 activation relative to cells derived from healthy patients. Expression of WT REV7 restored normal cellular and functional phenotypes in the patient's cells, and CRISPR/Cas9 inactivation of REV7 in a non-FA human cell line produced an FA phenotype. Finally, silencing Rev7 in primary hematopoietic cells impaired progenitor function, suggesting that the DNA repair defect underlies the development of BMF in FA. Taken together, our genetic and functional analyses identified REV7 as a previously undescribed FA gene, which we term FANCV.
authors: Dominique
authors: D
authors: Bluteau
authors: Julien
authors: J
authors: Masliah-Planchon
authors: Connor
authors: C
authors: Clairmont
authors: Alix
authors: A
authors: Rousseau
authors: Raphael
authors: R
authors: Ceccaldi
authors: Catherine
authors: C
authors: Dubois d'Enghien
authors: Olivier
authors: O
authors: Bluteau
authors: Wendy
authors: W
authors: Cuccuini
authors: Stéphanie
authors: S
authors: Gachet
authors: Régis
authors: R
authors: Peffault de Latour
authors: Thierry
authors: T
authors: Leblanc
authors: Gérard
authors: G
authors: Socié
authors: André
authors: A
authors: Baruchel
authors: Dominique
authors: D
authors: Stoppa-Lyonnet
authors: Alan D
authors: AD
authors: D'Andrea
authors: Jean
authors: J
authors: Soulier
mesh_terms: D000483:Alleles; D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002648:Child; D043171:Chromosomal Instability; D019457:Chromosome Breakage; D015331:Cohort Studies; D003432:Cross-Linking Reagents / Q000737:chemistry; D004249:DNA Damage; D004260:DNA Repair; D005199:Fanconi Anemia / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020868:Gene Silencing; D005816:Genetic Complementation Test; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D016086:Lentivirus; D064246:Mad2 Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D009154:Mutation; D010641:Phenotype
chemical_list: D003432:Cross-Linking Reagents; C120552:MAD2L2 protein, human; D064246:Mad2 Proteins; C577699:Mad2l2 protein, mouse