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Alu element insertion in PKLR gene as a novel cause of pyruvate kinase deficiency in Middle Eastern patients
Author(s) -
Lesmana Harry,
Dyer Lisa,
Li Xia,
Denton James,
Griffiths Jenna,
Chonat Satheesh,
Seu Katie G.,
Heeney Matthew M.,
Zhang Kejian,
Hopkin Robert J.,
Kalfa Theodosia A.
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23392
Subject(s) - biology , pyruvate kinase deficiency , alu element , missense mutation , exon , genetics , pyruvate kinase , gene , hemolytic anemia , mutation , genome , human genome , immunology , glycolysis , enzyme , biochemistry
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.