Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations
| Autor: | Montserrat Torrent, Maria Castella, Francis P. Lach, José Sánchez de Toledo, Antonia Rodríguez-Villa, Juan A. Bueren, Antonio Molinés, Julián Sevilla, Jesús Estella, Detlev Schindler, Elsa Callen, Muñoz A, Jordi Surrallés, A. Figuera, T Olivé, Javier Benitez, Beatriz Porto, Roser Pujol, Luis Madero, Juan P. Trujillo, Pedro Gómez, Cristina Beléndez, Arleen D. Auerbach, María Tapia, Teresa Ferro, Elena Cela, Angeles Dasí, Isabel Badell, José A. Casado, Hans J. J. P. Gille, José Barbot, Cristina Díaz de Heredia |
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| Přispěvatelé: | Human genetics, CCA - Oncogenesis |
| Rok vydání: | 2011 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Adolescent Clinical Trials and Observations Immunology Population DNA Mutational Analysis Molecular Sequence Data Cell Culture Techniques Biology medicine.disease_cause Biochemistry Models Biological 03 medical and health sciences 0302 clinical medicine Gene Frequency Fanconi anemia hemic and lymphatic diseases medicine Missense mutation Humans Allele Age of Onset education Child Cells Cultured 030304 developmental biology Genetics Chromosome Aberrations 0303 health sciences Mutation education.field_of_study Comparative Genomic Hybridization Base Sequence Fanconi Anemia Complementation Group A Protein nutritional and metabolic diseases Infant Cell Biology Hematology medicine.disease Phenotype FANCA 3. Good health Fanconi Anemia Spain 030220 oncology & carcinogenesis Child Preschool |
| Zdroj: | Castella, M, Pujol, R, Callen, E, Trujillo, J P, Casado, J A, Gille, J J P, Lach, F P, Auerbach, A D, Schindler, D, Benitez, J, Porto, B, Ferro, T, Munoz, A, Sevilla, J, Madero, L, Cela, E, Belendez, C, de Heredia, C D, Olive, T, de Toledo, J S, Badell, I, Torrent, M, Estella, J, Dasi, A, Rodriguez-Villa, A, Gomez, P, Barbot, J, Tapia, M, Molines, A, Figuera, A, Bueren, J A & Surralles, J 2011, ' Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations ', Blood, vol. 117, no. 14, pp. 3759-3769 . https://doi.org/10.1182/blood-2010-08-299917 Blood r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe instname BLOOD r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau Blood, 117(14), 3759-3769. American Society of Hematology |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Fanconi anemia is characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. To investigate the origin, functional role, and clinical impact of FANCA mutations, we determined a FANCA mutational spectrum with 130 pathogenic alleles. Some of these mutations were further characterized for their distribution in populations, mode of emergence, or functional consequences at cellular and clinical level. The world most frequent FANCA mutation is not the result of a mutational “hot-spot” but results from worldwide dissemination of an ancestral Indo-European mutation. We provide molecular evidence that total absence of FANCA in humans does not reduce embryonic viability, as the observed frequency of mutation carriers in the Gypsy population equals the expected by Hardy-Weinberg equilibrium. We also prove that long distance Alu-Alu recombination can cause Fanconi anemia by originating large interstitial deletions involving FANCA and 2 adjacent genes. Finally, we show that all missense mutations studied lead to an altered FANCA protein that is unable to relocate to the nucleus and activate the FA/BRCA pathway. This may explain the observed lack of correlation between type of FANCA mutation and cellular phenotype or clinical severity in terms of age of onset of hematologic disease or number of malformations. |
| Databáze: | OpenAIRE |
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