2017 March 24

Non-AUG start codons responsible for ABO weak blood group alleles on initiation mutant backgrounds

Dr. Emili Cid, a postdoctoral fellow at the Immunohematology and Glycobiology Group of the Josep Carreras Leukaemia Research Institute has published a paper in the journal Nature Scientific Reports.

Genetic information inscribed in the nucleotide sequence of DNA is transcribed into that of RNA, which is, in turn, translated into the amino acid sequence of protein. This flow is called the Central Dogma of Molecular Biology. The translation follows the conversion code of 3 nucleotides (triplets) into 1 of 20 amino acids or a termination codon. In animals the initiation of translation starts with a methionine codon (AUG). When this codon is mutated, proteins are not synthesized in most cases. However, in some cases proteins are still synthesized. It was believed that the next or one of the downstream methionine codons might have substituted the initiation role.

In this work, Dr. Cid and colleagues studied an enzyme called A glycosyltransferase that transfers a sugar to make the A antigen of the ABO blood groups, which is very important for blood transfusion. Many mutations were known of the ABO gene encoding this enzyme that altered the translation initiation codon by another amino acid (missense mutation) or inactivated the translation by terminating the protein synthesis early (nonsense mutation). But strangely, it was shown that several of them still exhibited weak expression of A antigens. So their enzymatic activity was not lost entirely. However, the molecular mechanism remained unknown.

The investigators prepared dozens of expression constructs containing a series of mutations and determined the expression of the A antigens. An unexpected and surprising finding was made. Rather than the methionine residue(s) downstream of the glycosyltransferase in the amino acid sequence, a non-methionine codon was used as the initiation codon of translation. In addition to this novel observation, they also demonstrated the importance of the transmembrane region of the enzyme for the enzymatic activity because the enzyme should be within the special location named Golgi apparatus within a cell in order to be functional.

Link to publication research: here