Bases moleculares de las alteraciones genéticas que afectan la síntesis de hemoglobina

• Autores: Scheps, Karen Gabriela
• Año de publicación: 2015
• Idioma: español castellano
• Tipo de recurso: tesis doctoral
• Colaborador/a o director/a de tesis: Varela, Viviana; Adamo, Ana; Chiappe, Gustavo; Slavutsky, Irma
• Materia: Hemoglobinopatías; Talasemia; Genética; Ciencia de la vida
• Institución: Universidad de Buenos Aires

Over 700 samples from carriers of structural hemoglobinopathies and thalassemia, and affected individuals with these syndromes, were analyzed.\nThe frequency of ?-thalassemia was updated: mutations were detected in 417 families; 9 mutations were described for the first time in Argentina.\nFive mutations associated with dominant forms of ?-thalassemia were detected: Hb Durham-N.C., and 4 novel mutations: Hbs Tavapy(HBB:c.182_187delCTCATG), JC-Paz(HBB:c.34_42delGTTACTGCC), Wilde (HBB:c.270_273delTGAG) and Patagonia(HBB:c.296_297dupGT).\nDeletions are the most common ?-thalassemic mutations (-?3,7, --MEDI, --CAL/CAMP and ?SEA). Three novel deletions were characterized: --BA, --PA and ?LU. The last one was identified in a boy with phenotypic features consistent with ATR-16. Point mutations were detected in both HBA genes; 3 novel mutations were detected: HBA1:c.301-2A>T, HBA1:c.187delG(p.W62fsX66) and HBA1:c.237delC(p.Asn78Lysfs*6).\nHb S is the most frequent structural hemoglobinopathy; mutations leading to unstable hemoglobins, hemoglobins with increased oxygen affinity and Hb M were detected, sporadically.\nGenotype-Phenotype association studies were performed to evaluate loci involved in Hb F levels variation.\nPrimary, secondary and tertiary genetic modifiers were analyzed in patients with thalassemia intermedia. Two novel ?-globin cluster duplications were detected.\nGenotype-Phenotype profiles were made and algorithms for molecular characterization were established.\nHopefully, this work will result in benefit of the affected families.
Fil: Scheps, Karen Gabriela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Se analizaron más de 700 muestras de pacientes con fenotipos hematológicos portadores de hemoglobinopatías estructurales, de talasemias menor, mayor y no transfusión dependiente.\nSe actualizó la frecuencia de ?-talasemia en 417 familias: 9 mutaciones se describieron por primera vez en Argentina.\nSe caracterizaron 5 mutaciones con fenotipo de talasemia dominante: Hb Durham-N.C., y 4 nóveles: Hbs Tavapy(HBB:c.182_187delCTCATG), JC-Paz(HBB:c.34_42delGTTACTGCC), Wilde (HBB:c.270_273delTGAG) y Patagonia(HBB:c.296_297dupGT).\nLas deleciones son las mutaciones ?-talasémicas más frecuentes (-?3,7, --MEDI, --CAL/CAMP y ?SEA). Se detectaron 3 deleciones nóveles: --BA, --PA y --LU, esta última en un paciente con retraso mental y rasgos de ATR-16. Se caracterizaron mutaciones puntuales, 3 nóveles: HBA1:c.301-2A>T, HBA1:c.187delG(p.W62fsX66) y HBA1:c.237delC(p.Asn78Lysfs*6).\nLa Hb S fue la hemoglobinopatía estructural prevalente y en forma esporádica se detectaron hemoglobinas inestables, con afinidad aumentada por el oxígeno y metahemoglobinas.\nSe hicieron estudios de asociación genotipo-fenotipo para marcadores asociados a variación de Hb F.\nEn pacientes con talasemia intermedia, se estudiaron modificadores primarios, secundarios y terciarios. Se detectaron 2 duplicaciones del cluster de ?-globina, una caracterizada por array-CGH, ((arr[hg19]Chr16(16p13.3; 88165- 230724)x3).\nSe confeccionaron perfiles genotipo-fenotipo, y algoritmos de trabajo para la caracterización molecular.\nSe espera que estos conocimientos sean en beneficio de las familias afectadas.
Doctora de la Universidad de Buenos Aires en Biología Molecular