title: Self-catalytic DNA depurination underlies human β-globin gene mutations at codon 6 that cause anemias and thalassemias.
abstract: The human β-globin gene contains an 18-nucleotide coding strand sequence centered at codon 6 and capable of forming a stem-loop structure that can self-catalyze depurination of the 5'G residue of that codon. The resultant apurinic lesion is subject to error-prone repair, consistent with the occurrence about this codon of mutations responsible for 6 anemias and β-thalassemias and additional substitutions without clinical consequences. The 4-residue loop of this stem-loop-forming sequence shows the highest incidence of mutation across the gene. The loop and first stem base pair-forming residues appeared early in the mammalian clade. The other stem-forming segments evolved more recently among primates, thereby conferring self-depurination capacity at codon 6. These observations indicate a conserved molecular mechanism leading to β-globin variants underlying phenotypic diversity and disease.
authors: Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
authors: Juan R
authors: JR
authors: Alvarez-Dominguez
authors: Olga
authors: O
authors: Amosova
authors: Jacques R
authors: JR
authors: Fresco
mesh_terms: D000740:Anemia / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003062:Codon; D004247:DNA / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009690:Nucleic Acid Conformation; D013789:Thalassemia / Q000235:genetics / Q000378:metabolism; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: D003062:Codon; D055544:beta-Globins; D004247:DNA