Resumen
La ferritina es una proteína altamente conservada, pero las mutaciones en su secuencia primaria pueden estar relacionadas con diversas enfermedades, entre ellas, la hiperferritinemia con cataratas asociada a la mutación con cambio de sentido T30I en la ferritina de cadena ligera. Aunque se han propuesto algunos de los mecanismos moleculares de dicha mutación, el papel de las modificaciones postraduccionales involucradas aún no se ha esclarecido completamente. Hacemos aquí una caracterización bioinformática de las modificaciones alteradas por la mutación utilizando bases de datos y programas predictivos como NetNGlyc 1.0, NetOGlyc 4.0, NETPHOS 3.1 y Reactome. Nuestros análisis apuntaron hacia la pérdida de fosforilación en la serina 33 por acción de la quinasa CKI, lo que afecta la vía de señalización Wnt/β-catenina. Estos resultados nos permiten proponer que la alteración en las modificaciones postraduccionales de la ferritina de cadena ligera constituiría un mecanismo molecular relacionado con el desarrollo de cataratas en la hiperferritinemia hereditaria.
Referencias
Amit, S., Hatzubai, A., Birman, Y., Andersen, J. S., Ben-Shushan, E., Mann, M., Ben-Neriah, Y., Alkalay, I. (2002). Axin-mediated CKI phosphorylation of β-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes & Development, 16(9), 1066-1076. https://doi.org/10.1101/GAD.230302
Beaumont, C., Leneuve, P., Devaux, I., Scoazec, J. Y., Berthier, M., Loiseau, M. N., Grandchamp, B., Bonneau, D. (1995). Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract. Nature Genetics, 11(4), 444-446. https://doi.org/10.1038/NG1295-444;KWRD
Blom, N., Gammeltoft, S., Brunak, S. (1999). Sequence- and structure-based prediction of eukaryotic protein phosphorylation sites. Journal of Molecular Biology, 294(5), 1351-1362.
Blom, N., Sicheritz-Ponten, T., Gupta, R., Gammeltoft, S., Brunak, S. (2004). Prediction of posttranslational glycosylation and phosphorylation of proteins from the amino acid sequence. Proteomics, 4(6), 1633-1649.
Brooks, D., Todorova, K., Farmer, J., Lobmayr, L., Wilson, R., Eagle, R. (2002). Ferritin Crystal Cataracts in Hereditary Hyperferritinemia Cataract Syndrome. Investigative Ophthalmology & Visual Science, 43(4), 1121-1126. https://iovs.arvojournals.org/article.aspx?articleid=2200177
Carrillo-Esper, R., Peña-Pérez, C., Zepeda-Mendoza, A. D., Meza-Márquez, J. M., Neri-Maldonado, R., Meza-Ayala, C. M., Carrillo-Córdova, D. M., Carrillo-Córdova, C. A. (2015). Ferritina y síndrome hiperferritinémico. Su impacto en el enfermo grave; conceptos actuales. Revista de La Asociación Mexicana de Medicina Critica y Terapia Intensiva, 29(3), 157-166. http://www.scielo.org.mx/pdf/rammcti/v29n3/v29n3a6.pdf
Chang-Godinich, A., Ades, S., Schenkein, D., Brooks, D., Stambolian, D., Raizman, M. B. (2001). Lens changes in hereditary hyperferritinemia-cataract syndrome. American Journal of Ophthalmology, 132(5), 786-788. https://doi.org/10.1016/S0002-9394(01)01106-0
Craig, J., Clark, B., McLeod, J., Kirkland, M., Grant, G., Elder, J., Toohey, M., Kowal, L., Savoia, H., Chen, C., Roberts, S., Wirth, G., Mackey, D. (2003a). Hereditary Hyperferritinemia-Cataract Syndrome: Prevalence, Lens Morphology, Spectrum of Mutations, and Clinical Presentations. Archives of Ophthalmology, 121(12), 1753-1761. https://doi.org/10.1001/ARCHOPHT.121.12.1753
Craig, J., Clark, J. B., McLeod, J., Kirkland, M., Grant, G., Elder, J., Toohey, M., Kowal, L., Savoia, H., Chen, C., Roberts, S., Wirth, M. G., Mackey, D. (2003b). Hereditary Hyperferritinemia-Cataract Syndrome: Prevalence, Lens Morphology, Spectrum of Mutations, and Clinical Presentations. Archives of Ophthalmology, 121(12), 1753-1761. https://doi.org/10.1001/ARCHOPHT.121.12.1753
Elsayed, M. E., Sharif, M. U., Stack, A. G. (2016). Transferrin Saturation: A Body Iron Biomarker. Advances in Clinical Chemistry, 75, 71-97. https://doi.org/10.1016/BS.ACC.2016.03.002
Eris, T., Yanik, A. M., Demirtas, D., Yilmaz, A. F., Toptas, T. (2023). Hereditary Hyperferritinemia-Cataract Syndrome in a Family With HFE-H63D Mutation. Cureus, 15(3), e36253. https://doi.org/10.7759/CUREUS.36253
Fabregat, A., Korninger, F., Viteri, G., Sidiropoulos, K., Marin-Garcia, P., Ping, P., Wu, G., Stein, L., D’Eustachio, P., Hermjakob, H. (2018). Reactome graph database: Efficient access to complex pathway data. PLoS Computational Biology, 14(1), e1005968. https://doi.org/10.1371/JOURNAL.PCBI.1005968
Fujimura, N. (2016). WNT/β-catenin signaling in vertebrate eye development. Frontiers in Cell and Developmental Biology, 4(NOV), 221674. https://doi.org/10.3389/FCELL.2016.00138/BIBTEX
Giansily-Blaizot, M., Cunat, S., Moulis, G., Schved, J. F., Aguilar-Martínez, P. (2013). Homozygous mutation of the 5’UTR region of the L-Ferritin gene in the hereditary hyperferritinemia cataract syndrome and its impact on the phenotype. Haematologica, 98(4), e43. https://doi.org/10.3324/HAEMATOL.2012.077198
Girelli, D., Ouvieri, O., Franceschi, L. De, Corrocher, R., Bergamaschi, G., Cazzola, M. (1995). A linkage between hereditary hyperferritinaemia not related to iron overload and autosomal dominant congenital cataract. British Journal of Haematology, 90(4), 931-934. https://doi.org/10.1111/J.1365-2141.1995.TB05218.X
Gómez-Hernández, M., Soto-Ospina, A., Osorio, C. A., Villegas-Lanau, A. (2024). Structural Analysis of Variants of the Ferritin Light Chain Protein and Its Relationship with Neuroferritinopathy. ACS Chemical Neuroscience, 15(24), 4402-4417. https://doi.org/10.1021/ACSCHEMNEURO.4C00400
Gupta, R. & Brunak, S. (2002). Prediction of glycosylation across the human proteome and the correlation to protein function. Pacific Symposium on Biocomputing, 2002, 310-322.
Iqbal, H., Yang, T., Li, T., Zhanga, M., Ke, H., Ding, D., Deng, Y., Chen, H. (2021). Serum proteinbased nanoparticles for cancer diagnosis and treatment. Journal of Controlled Release, 329, 997-1022. https://doi.org/10.1016/j.jconrel.2020.10.030
Kaarniranta, K., Zin, O. A., Neves, L. M., Cunha, D. P., Motta, F. L., Agonigi, B. N. S., Horovitz, D. D. G., Almeida, D. C., Malacarne, J., Paula, A., Rodrigues, S., Carvalho, A. B., Rivello, C. A., Espariz, R., Zin, A. A., Sallum, J. M. F., Vasconcelos, Z. F. M., Br, A. Z. (2023). Genotypic-Phenotypic Correlations of Hereditary Hyperferritinemia-Cataract Syndrome: Case Series of Three Brazilian Families. International Journal of Molecular Sciences, 24(15). https://doi.org/10.3390/ijms241511876
Kannengiesser, C., Jouanolle, A. M., Hetet, G., Mosser, A., Muzeau, F., Henry, D., Bardou-Jacquet, E., Mornet, M., Brissot, P., Deugnier, Y., Grandchamp, B., Beaumont, C. (2009). A new missense mutation in the L ferritin coding sequence associated with elevated levels of glycosylated ferritin in serum and absence of iron overload. Haematologica, 94(3), 335-339. https://doi.org/10.3324/HAEMATOL.2008.000125
Khan, M. A., Mohammad, T., Malik, A., Hassan, M. I., Domashevskiy, A. V. (2023). Iron response elements (IREs)-mRNA of Alzheimer’s amyloid precursor protein binding to iron regulatory protein (IRP1): a combined molecular docking and spectroscopic approach. Scientific Reports, 13(1), 1-17. https://doi.org/10.1038/S41598-023-32073-X;SUBJMETA
Lachlan, K. L., Temple, I. K., Mumford, A. D. (2004). Clinical features and molecular analysis of seven British kindreds with hereditary hyperferritinaemia cataract syndrome. European Journal of Human Genetics 2004 12:10, 12(10), 790-796. https://doi.org/10.1038/sj.ejhg.5201252
Liu, C., Li, Y., Semenov, M., Han, C., Baeg, G. H., Tan, Y., Zhang, Z., Lin, X., He, X. (2002). Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell, 108(6), 837-847. https://doi.org/10.1016/S0092-8674(02)00685-2
Milacic, M., Beavers, D., Conley, P., Gong, C., Gillespie, M., Griss, J., Haw, R., Jassal, B., Matthews, L., May, B., Petryszak, R., Ragueneau, E., Rothfels, K., Sevilla, C., Shamovsky, V., Stephan, R., Tiwari, K., Varusai, T., Weiser, J., … D’Eustachio, P. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research, 52(D1), D672-D678. https://doi.org/10.1093/NAR/GKAD1025
Moravikova, J., Honzik, T., Jadvidzakova, E., Zdrahalova, K., Kremlikova Pourova, R., Korbasova, M., Liskova, P., Dudakova, L. (2020). Hereditary hyperferritinemia-cataract syndrome in three Czech families: molecular genetic testing and clinical implications. Journal of American Association for Pediatric Ophthalmology and Strabismus, 24(6), 352.e1-352.e5. https://doi.org/10.1016/J.JAAPOS.2020.07.014
Neves, J., Haider, T., Gassmann, M., Muckenthaler, M. U. (2019). Iron Homeostasis in the Lungs—A Balance between Health and Disease. Pharmaceuticals, 12(1), 5. https://doi.org/10.3390/PH12010005
Nos, F., Hernández, G., Ferrer, X., Hernandez, I., Navarro, B., Fuster, J. L., Cortés, M. B., Pérez, S., Tornador, C., Sánchez, M. (2021). Hereditary hyperferritinemia cataract syndrome: Ferritin l gene and physiopathology behind the disease—report of new cases. International Journal of Molecular Sciences, 22(11), 5451. https://doi.org/10.3390/IJMS22115451/S1
Sandnes, M., Ulvik, R. J., Vorland, M., Reikvam, H. (2021). Hyperferritinemia—A Clinical Overview. Journal of Clinical Medicine, 10(9), 2008. https://doi.org/10.3390/JCM10092008
Steentoft, C., Vakhrushev, S., Joshi, H., Kong, Y., Vester-Christensen, M., Schjoldager, K., Lavrsen, K., Dabelsteen, S., Pedersen, N., Gupta, R., Bennett, E., Mandel, U., Brunak, S., Wandall, H., Levery, S., Clausen, H. (2013). Precision mapping of the human O-GalNAc glycoproteome through SimpleCell technology. EMBO J, 32(10), 1478-1488.
Torti, F. M. & Torti, S. V. (2002). Regulation of ferritin genes and protein. Blood, 99(10), 3505-3516. https://doi.org/10.1182/BLOOD.V99.10.3505
Yang, Y., Lin, T., Kuang, P., Chen, X. (2021). Ferritin L-subunit gene mutation and hereditary hyperferritinaemia cataract syndrome (HHCS): a case report and literature review. Hematology (United Kingdom), 26(1), 896-903. https://doi.org/10.1080/16078454.2021.1995111
Esta obra está bajo una licencia internacional Creative Commons Atribución-NoComercial-SinDerivadas 4.0.
Derechos de autor 2025 Revista de la Academia Colombiana de Ciencias Exactas, Físicas y Naturales