Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency

The first known human case of heme oxygenase-1 (HO-1) deficiency is present ed in this report. The patient is a six-year-old boy with severe growth ret ardation. He has been suffering from persistent hemolytic anemia characteri zed by marked erythrocyte fragmentation and intravascular hemolysis, with p aradoxical increase of serum haptoglobin and low bilirubin. An abnormal coa gulation/fibrinolysis system, associated with elevated thrombomodulin and v on Willebrand factor, indicated the presence of severe, persistent endothel ial damage. Electron microscopy of renal glomeruli revealed detachment of e ndothelium, with subendothelial deposition of an unidentified material. Iro n deposition was noted in renal and hepatic tissue. Immunohistochemistry of hepatic tissue and immunoblotting of a cadmium-stimulated Epstein-Barr vir us-transformed lymphoblastoid cell line (LCL) revealed complete absence of HO-1 production. An LCL derived from the patient was extremely sensitive to hemin-induced cell injury. Sequence analysis of the patient's HO-1 gene re vealed complete loss of exon-2 of the maternal allele and a two-nucleotide deletion within exon3 of the paternal allele. Growth retardation, anemia, i ron deposition, and vulnerability to stressful injury are all characteristi cs observed in recently described HO-1 targeted mice. This study presents n ot only the first human case of HO-1 deficiency but may also provide clues to the key roles played by this important enzyme in vivo.