Alu element insertion in PKLR gene as a novel cause of pyruvate kinase deficiency in Middle Eastern patients. Issue 3 (11th January 2018) - Lesmana, Harry
Abstract: Pyruvate kinase deficiency (PKD) is the most frequent red blood cell enzyme abnormality of the glycolytic pathway and the most common cause of hereditary nonspherocytic hemolytic anemia. Over 250 PKLR ‐gene mutations have been described, including missense/nonsense, splicing and regulatory mutations, small insertions, small and gross deletions, causing PKD and hemolytic anemia of variable severity. Alu retrotransposons are the most abundant mobile DNA sequences in the human genome, contributing to almost 11% of its mass. Alu insertions have been associated with a number of human diseases either by disrupting a coding region or a splice signal. Here, we report on two unrelated Middle Eastern patients, both born from consanguineous parents, with transfusion‐dependent hemolytic anemia, where sequence analysis revealed a homozygous insertion of AluYb9 within exon 6 of the PKLR gene, causing precipitous decrease of PKLR RNA levels. This Alu element insertion consists a previously unrecognized mechanism underlying pathogenesis of PKD. Abstract : A pathogenic PKLR gene mutation from an Alu element insertion was identified in two unrelated families from Middle East, implicating the possibility of a founder insertion event in the Arab population, as a novel cause of pyruvate kinase deficiency. Both patients were born from consanguineous parents and presented with transfusion‐dependent hemolytic anemia. Sequence analysis revealed a homozygous insertion of AluYb9 within exon 6 of PKLR, leading to premature termination of the mutant transcript and precipitous decrease of PKLR RNA levels.