CHARACTERIZATION OF MISSENSE MUTATIONS AND BIOCHEMICAL ANALYSIS OF INCREASED LIPID PEROXIDATION AND MITOCHONDRIAL DYSFUNCTION IN ACERULOPLASMINEMIA

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Aceruloplasminemia, an autosomal recessive disorder that affects iron metabolism, is caused by mutations of the ceruloplasmin gene. It is characterized by iron accumulation in the brain as well as visceral organs. Clinically, the disease consists of the triad of retinal degeneration, diabetes mellitus, and neurologic disease. Almost all the mutations in the ceruloplasmin gene reported previously were truncation mutations. To elucidate the molecular pathogenesis of aceruloplasminemia, the ceruloplasmin biosynthesis of two missense mutants was examined. A P177R mutation results in the location of ceruloplasmin within the endoplasmic reticulum as apoprotein. An H978Q mutation results in detectable serum ceruloplasmin devoid of ferroxidase activity associated with decreased copper incorporation.The unique involvement of the central nervous system distinguishes aceruloplasminemia from other inherited and acquired iron storage disorders. Excess iron functions as a potent catalyst of biologic oxidation. We showed that an increased iron concentration is associated with increased lipid peroxidation in the brains of three aceruloplasminemia patients. Positron emission tomography showed cortical glucose and oxygen hypometabolism. Enzyme activities in the mitochondrial respiratory chain of the basal ganglia were reduced to about 50% and 43% respectively for complexes I and IV. Those of the cerebral and cerebellar cortices also were decreased approximately 62% and 65%. These findings suggest that iron-mediated free radicals may contribute to increased lipid peroxidation and the impairment of mitochondrial energy metabolism in aceruloplasminemia brains.