Biallelic inactivation of REV7 is associated with Fanconi anemia

Bluteau, Dominique; Masliah‐Planchon, Julien; Clairmont, Connor S.; Rousseau, Alix; Ceccaldi, Raphaël; d’Enghien, Catherine Dubois; Bluteau, Olivier; Cuccuini, Wendy; Gachet, Stéphanie; Latour, Régis Peffault de; Leblanc, Thierry; Socié, Gérard; Baruchel, André; Stoppa‐Lyonnet, Dominique; D’Andrea, Alan D.; Soulier, Jean

doi:10.1172/jci88010

Cited by 120 publications

(89 citation statements)

References 31 publications

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“…Other frequent aspects of FA comprise early-onset bone marrow failure and cancer predisposition, specifically for acute myelogenous leukemia and head and neck squamous cell carcinoma (1)(2)(3)(4). FA results from faults in the FA/BRCA pathway for DNA interstrand cross-link (ICL) repair, in which proteins encoded by 21 FA genes reported thus far -designated as or aliased with the prefix FANC-and serial letters of the alphabet, FANCA to FANCV -and associated proteins interact (5)(6)(7)(8)(9). Germline inactivation of any one of the FA genes causes classical FA or variant (FA-like) disease lacking single clinical core features of FA.…”

Section: Introductionmentioning

confidence: 99%

“…The FA/ BRCA pathway orchestrates the action of other DNA repair proteins such as nucleases, translesion polymerases, and effectors of homologous recombination (HR), and interfaces with other DNA repair networks with which it shares components. New elements of the FA/BRCA pathway continue to be identified in ways that keep our understanding of this pathway evolving (5,(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

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Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Knies¹,

Inano²,

Ramı́rez³

et al. 2017

Journal of Clinical Investigation

177

171

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The WD40-containing E3 ubiquitin ligase RFWD3 has been recently linked to the repair of DNA damage by homologous recombination (HR). Here we have shown that an RFWD3 mutation within the WD40 domain is connected to the genetic disease Fanconi anemia (FA). An individual presented with congenital abnormalities characteristic of FA. Cells from the patient carrying the compound heterozygous mutations c.205_206dupCC and c.1916T>A in RFWD3 showed increased sensitivity to DNA interstrand cross-linking agents in terms of increased chromosomal breakage, reduced survival, and cell cycle arrest in G 2 phase. The cellular phenotype was mirrored in genetically engineered human and avian cells by inactivation of RFWD3 or introduction of the patient-derived missense mutation, and the phenotype was rescued by expression of wild-type RFWD3 protein. HR was disrupted in RFWD3-mutant cells as a result of impaired relocation of mutant RFWD3 to chromatin and defective physical interaction with replication protein A. Rfwd3 knockout mice appear to have increased embryonic lethality, are subfertile, show ovarian and testicular atrophy, and have a reduced lifespan resembling that of other FA mouse models. Although RFWD3 mutations have thus far been detected in a single child with FA, we propose RFWD3 as an FA gene, FANCW, supported by cellular paradigm systems and an animal model.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Knies¹,

Inano²,

Ramı́rez³

et al. 2017

Journal of Clinical Investigation

177

171

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“…1 Mutations in at least 20 genes in pathways involved in DNA damage sensing and repair have been described in association with a Fanconi phenotype. [2][3][4][5] Impaired DNA repair leads to clinically significant chemotherapy and radiation sensitivity, making delivery of the preparative regimen for allogeneic hematopoietic cell transplantation (HCT), the only curative option for the hematologic complications of patients with FA, challenging. [6][7][8] Initial efforts at HCT for FA in the late 1970s and early 1980s demonstrated excessive toxicity and high mortality rates.…”

Section: Introductionmentioning

confidence: 99%

Radiation-free, alternative-donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study

Mehta

Davies

Leemhuis

et al. 2017

Blood

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• Alternative donor HCT can be performed in patients with FA without using radiation.• All 26 patients younger than 10 years of age undergoing HCT for marrow failure using lower-dose busulfancontaining regimen survived.Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by chromosomal fragility, progressive marrow failure, and cancer predisposition. Hematopoietic cell transplantation (HCT) is curative for FA-related marrow failure or leukemia, but both radiation exposure during transplant and graft-versus-host disease (GVHD) may increase risk of later malignancies of the head and neck and anogenital area. In this study, we tested a radiation-free conditioning regimen with a T-cell-depleted graft to eliminate radiation exposure and minimize early and late toxicities of transplant. Forty-five patients (median age, 8.2 years; range 4.3-44) with FA underwent HCT between June 2009 and May 2014. The preparative regimen included busulfan, cyclophosphamide, fludarabine, and rabbit anti-thymocyte globulin. Busulfan levels were monitored to avoid excess toxicity. All grafts were CD34-selected/T-cell-depleted using the CliniMacs CD34 columns (Miltenyi). Thirty-four patients (75.6%) with marrow failure and 11 (24.4%) with myelodysplastic syndrome underwent HCT using matched unrelated (n 5 25, 55.5%), mismatched unrelated (n 5 14, 31.1%), or mismatched related donors (n 5 6, 13.4%). One year probabilities of overall and disease-free survival for the entire cohort, including patients with myeloid malignancy and those receiving mismatched related/haploidentical grafts, were 80% (66%) and 77.7% (66.2%), respectively (median follow-up 41 months). All young children (<10 years of age) undergoing HCT for marrow failure using low-dose busulfancontaining regimen survived. No patients developed acute grade 3-4 GVHD. Sequential reduction of busulfan dose was successfully achieved per study design. Our results show excellent outcomes in patients with FA undergoing alternative donor HCT without radiation exposure. The study is registered to www.clinicaltrials.gov as #NCT01082133. (Blood. 2017;129(16):2308-2315

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“…The more common genes are FANCA, FANCB, FANC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, and FANCJ (BRIP1). The less common FA genes include; FANCL, FANCM, FANCN (PALB2), FANCO (RAD51C), FANCP (SLX4), FANCQ (ERCC4), FANCR (RAD51), FANCT (UBE2T), FANCU (XRCC2), and FANCV(MAD2L2) [3,4]. FNAC-G has been localized to the short arm of chromosome p923.…”

Section: Discussionmentioning

confidence: 99%