PKLR mutations in pyruvate kinase deficient Polish patients: Functional characteristics of c.101-1G > A and c.1058delAAG variants

Pyruvate kinase (PK) deficiency is a rare autosomal recessive disorder characterized by chronic hemolytic anemia of variable severity. Nine Polish patients with severe hemolytic anemia but normal PK activity were found to carry mutations in the PKLR gene encoding PK, five already known ones and one novel (c.178C > T). We characterized two of the known variants by molecular modeling (c.1058delAAG) and minigene splicing analysis (c.101-1G > A). The former gives a partially destabilized PK tetramer, likely of suboptimal activity, and the c.101-1G > A variant gives alternatively spliced mRNA carrying a premature stop codon, encoding a severely truncated PK and likely undergoing nonsense-mediated decay.