RESUMO
We report a clinical update of the hemoglobin (Hb) variant [ß27(B9)AlaâGly; HBB: c.83C>G], named Hb Siirt, that was previously described as a silent variant in a 23-year-old Kurdish female. The patient was also a carrier of the codon 5 (-CT) (HBB: c.17_18delCT) frameshift mutation and of the ααα anti 3.7 triplication. Her initial moderate ß-thalassemia intermedia (ß-TI) phenotype worsened with time, causing the patient to become a transfusion-dependent subject at the age of â¼40 years. Subsequent molecular characterization of both parents revealed that the Hb Siirt variant was inherited by the mother, while the other two globin alterations (HBB: c.17_18delCT and αααanti 3.7 triplication) were genetically transmitted by the father. The latter remained a carrier of a mild ß-TI phenotype throughout his life, at least until the age of 65 years. We hypothesize that the worsened clinical conditions in the daughter were due to the additional, maternally inherited Hb Siirt variant. However, protein 3D conformational analysis did not seem to reveal substantial overall structural changes. Among the other three described variants [Hb Volga (HBB: c.83C>A), Hb Knossos (HBB: c.82 G>T), Hb Grange-Blanche (HBB: c.83C>T] that are due to nucleotide substitutions at codon 27 of the ß-globin gene; only Hb Knossos causes a ß+-thalassemia (ß+-thal) phenotype.
Assuntos
Alelos , Substituição de Aminoácidos , Códon , Hemoglobinas Anormais/genética , Globinas beta/genética , Índices de Eritrócitos , Feminino , Estudos de Associação Genética , Genótipo , Heme/química , Heme/metabolismo , Hemoglobinas Anormais/química , Hemoglobinas Anormais/metabolismo , Heterozigoto , Humanos , Modelos Moleculares , Conformação Molecular , Oxigênio/metabolismo , Fenótipo , Ligação Proteica , Adulto Jovem , alfa-Globinas/genética , Globinas beta/química , Globinas beta/metabolismo , Talassemia beta/sangue , Talassemia beta/diagnóstico , Talassemia beta/genéticaRESUMO
Eukaryotic topoisomerase I is an essential enzyme that regulates the changes in DNA topology, relaxing the superhelical tension associated with DNA replication, transcription and recombination. Human topoisomerase I is of significant medical interest being the only target of the antitumor drug camptothecin. The enzyme undergoes large conformational changes during its catalytic cycle and the knowedge of the degree of flexibility of the different regions provides an useful guide to the understanding of such movements. Molecular dynamics simulation is a well consolidated method for the investigation of structural and dynamic properties of proteins and nucleic acids and has been successfully applied to study the dynamical properties of the DNA-human topoisomerase complex. This review highlights some structural and dynamic properties of topoisomerase, obtained by MD simulations, that permits to explain the importance of flexibility in the modulation of the functional properties of the enzyme and in the transmission of communication between domains located far away one from each other.
