TY - JOUR
T1 - A Homozygous Mutation on the HBA1 Gene Coding for Hb Charlieu (HBA1: c.320T>C) Together with β-Thalassemia Trait Results in Severe Hemolytic Anemia
AU - Klei, Thomas R. L.
AU - Kheradmand Kia, Sima
AU - Veldthuis, Martijn
AU - Dehbozorgian, Javad
AU - Karimi, Mehran
AU - Geissler, Judy
AU - Sellink, Erica
AU - Thiel-Valkhof, Marijke
AU - Burger, Patrick
AU - van Alphen, Floris
AU - Meijer, Alexander B.
AU - van Bruggen, Robin
AU - van Zwieten, Rob
PY - 2019
Y1 - 2019
N2 - A 4-year-old boy, a β-thalassemia (β-thal) carrier, with an unexplained severe chronic microcytic anemia was referred to us. Sequencing of the α-globin genes revealed a Hb Charlieu [α106(G13)Leu→Pro, HBA1: c.320T>C, p.Leu107Pro] mutation present on both HBA1 genes. Quantitative polymerase chain reaction (qPCR) confirmed αCharlieu mRNA in the proband and his parents, showing that the mutation does not affect mRNA stability. However, we were unable to detect the Hb Charlieu protein by capillary electrophoresis (CE), reverse phase electrophoresis, cation exchange electrophoresis or isoelectric focusing. Mass spectrometry (MS) allowed us to confirm the presence of the Hb Charlieu peptide in erythrocyte progenitors. These findings suggest that the mutation affects the stability of αCharlieu. As hemoglobin (Hb) heat stability tests showed no abnormalities in erythrocytes, we speculated that αCharlieu is already degraded during red blood cell (RBC) development. The clinical severity in the proband and the presence of new methylene blue-stained aggregates in his reticulocytes indicates that incorporation of αCharlieu destabilizes Hb. This, combined with an excess of unstable free α-globins as the result of β-thal minor, results in severely impaired erythropoiesis and, as a consequence, severe and chronic microcytic anemia in the proband.
AB - A 4-year-old boy, a β-thalassemia (β-thal) carrier, with an unexplained severe chronic microcytic anemia was referred to us. Sequencing of the α-globin genes revealed a Hb Charlieu [α106(G13)Leu→Pro, HBA1: c.320T>C, p.Leu107Pro] mutation present on both HBA1 genes. Quantitative polymerase chain reaction (qPCR) confirmed αCharlieu mRNA in the proband and his parents, showing that the mutation does not affect mRNA stability. However, we were unable to detect the Hb Charlieu protein by capillary electrophoresis (CE), reverse phase electrophoresis, cation exchange electrophoresis or isoelectric focusing. Mass spectrometry (MS) allowed us to confirm the presence of the Hb Charlieu peptide in erythrocyte progenitors. These findings suggest that the mutation affects the stability of αCharlieu. As hemoglobin (Hb) heat stability tests showed no abnormalities in erythrocytes, we speculated that αCharlieu is already degraded during red blood cell (RBC) development. The clinical severity in the proband and the presence of new methylene blue-stained aggregates in his reticulocytes indicates that incorporation of αCharlieu destabilizes Hb. This, combined with an excess of unstable free α-globins as the result of β-thal minor, results in severely impaired erythropoiesis and, as a consequence, severe and chronic microcytic anemia in the proband.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85067456711&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31190578
U2 - https://doi.org/10.1080/03630269.2019.1601107
DO - https://doi.org/10.1080/03630269.2019.1601107
M3 - Article
C2 - 31190578
SN - 0363-0269
VL - 43
SP - 77
EP - 82
JO - Hemoglobin
JF - Hemoglobin
IS - 2
ER -