Alu element insertion in PKLR gene as a novel cause of pyruvate kinase deficiency in Middle Eastern patients

• Authors: Harry Lesmana, University of Cincinnati; Lisa Dyer, University of Cincinnati; Xia Li, University of Cincinnati; James Denton, University of Cincinnati; Jenna Griffiths, University of Cincinnati; Satheesh Chonat, Emory University; Katie G. Seu, University of Cincinnati; Matthew M. Heeney, Harvard Medical School; Kejian Zhang, University of Cincinnati; Robert J. Hopkin, University of Cincinnati; Theodosia A. Kalfa, University of Cincinnati
• Journal Title: Human Mutation
• Volume: Volume 39, Number 3
• Publisher: Wiley: 12 months | 2018-03-01, Pages 389-393
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1002/humu.23392
• Subjects: Biology, Genetics; Health Sciences, Oncology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Genetics & Heredity; AluYb9; hemolytic anemia; insertion mutation; PKLR; pyruvate kinase deficiency; retrotransposon; transposable element; HEREDITARY HEMOLYTIC-ANEMIA; TRANSPOSABLE ELEMENTS; POPULATION; PREVALENCE; DISORDERS; MUTATION; DISEASES; DATABASE

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.