RESUMEN
Fanconi anemia (FA) is a rare inherited disorder caused by pathogenic variants in one of 19 FANC genes. FA patients display congenital abnormalities, and develop bone marrow failure, and cancer susceptibility. We identified homozygous mutations in four FA patients and, in each case, only one parent carried the obligate mutant allele. FANCA and FANCP/SLX4 genes, both located on chromosome 16, were the affected recessive FA genes in three and one family respectively. Genotyping with short tandem repeat markers and SNP arrays revealed uniparental disomy (UPD) of the entire mutation-carrying chromosome 16 in all four patients. One FANCA patient had paternal UPD, whereas FA in the other three patients resulted from maternal UPD. These are the first reported cases of UPD as a cause of FA. UPD indicates a reduced risk of having another child with FA in the family and has implications in prenatal diagnosis.
Asunto(s)
Cromosomas Humanos Par 16/genética , Proteína del Grupo de Complementación A de la Anemia de Fanconi/genética , Anemia de Fanconi/genética , Recombinasas/genética , Disomía Uniparental/genética , Adulto , Preescolar , Femenino , Genes Recesivos , Homocigoto , Humanos , Masculino , Mutación , Linaje , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
Repair of DNA interstrand crosslinks requires action of multiple DNA repair pathways, including homologous recombination. Here, we report a de novo heterozygous T131P mutation in RAD51/FANCR, the key recombinase essential for homologous recombination, in a patient with Fanconi anemia-like phenotype. In vitro, RAD51-T131P displays DNA-independent ATPase activity, no DNA pairing capacity, and a co-dominant-negative effect on RAD51 recombinase function. However, the patient cells are homologous recombination proficient due to the low ratio of mutant to wild-type RAD51 in cells. Instead, patient cells are sensitive to crosslinking agents and display hyperphosphorylation of Replication Protein A due to increased activity of DNA2 and WRN at the DNA interstrand crosslinks. Thus, proper RAD51 function is important during DNA interstrand crosslink repair outside of homologous recombination. Our study provides a molecular basis for how RAD51 and its associated factors may operate in a homologous recombination-independent manner to maintain genomic integrity.
Asunto(s)
Reparación del ADN , ADN/metabolismo , Anemia de Fanconi/genética , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismo , Proteína de Replicación A/metabolismo , Supervivencia Celular , Reactivos de Enlaces Cruzados , ADN Helicasas/metabolismo , Exodesoxirribonucleasas/metabolismo , Anemia de Fanconi/metabolismo , Femenino , Inestabilidad Genómica , Células HEK293 , Heterocigoto , Humanos , Lactante , Mutación , RecQ Helicasas/metabolismo , Helicasa del Síndrome de WernerRESUMEN
Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT.
Asunto(s)
Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/metabolismo , Proteína del Grupo de Complementación L de la Anemia de Fanconi/metabolismo , Anemia de Fanconi/genética , Enzimas Ubiquitina-Conjugadoras/metabolismo , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/genética , Proteína del Grupo de Complementación L de la Anemia de Fanconi/genética , Fibroblastos/metabolismo , Eliminación de Gen , Células HEK293 , Humanos , Unión Proteica , Enzimas Ubiquitina-Conjugadoras/deficiencia , Enzimas Ubiquitina-Conjugadoras/genética , UbiquitinaciónRESUMEN
Fanconi anemia (FA) is the most common of the inherited bone marrow failure syndromes with an incidence of approximately 1/100,000 to 1/200,000 live births. FA is a genetically complex and phenotypically heterogeneous condition involving birth defects, bone marrow failure, and cancer predisposition. This rare disease became well known in the genetic counseling community in 2002, when it was identified that biallelic mutations in BRCA2 can cause FA. Knowledge gained from the growing association between FA and breast cancer pathways has brought even more light to the complex genetic issues that arise when counseling families affected by this disease. Genetic counseling issues surrounding a diagnosis of FA affect many different disciplines. This review will serve as a way to cross-link the various topics important to genetic counselors that arise throughout the life of a patient with FA. Issues covered will include: an overview of FA, phenotypic presentation, management and treatment, the genetics and inheritance of FA, cytogenetic and molecular testing options, and the risks to family members of an individual with FA.
