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Hiroaki Miyajima – One of the best experts on this subject based on the ideXlab platform.

Kunihiro Yoshida – One of the best experts on this subject based on the ideXlab platform.

Jonathan D. Gitlin – One of the best experts on this subject based on the ideXlab platform.

  • The copper-iron connection: Hereditary Aceruloplasminemia
    Seminars in hematology, 2002
    Co-Authors: Thalia Nittis, Jonathan D. Gitlin
    Abstract:

    Abstract Hereditary Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis due to loss-of-function mutations in the ceruloplasmin gene. Affected individuals may present in adulthood with evidence of hepatic iron overload, diabetes, peripheral retinal degeneration, dystonia, dementia, or dysarthria. Laboratory studies demonstrate microcytic anemia, elevated serum ferritin, and a complete absence of serum ceruloplasmin ferroxidase activity. Consistent with the observed neurologic findings, magnetic resoresonanceging reveals iron accumulation within the basal ganglia. Histologic studies detect abundant iron in hepatocytes, reticuloendothelial cells of the liver and spleen, β cells of the pancreas, and astrocytes and neurons throughout the central nervous system. Characterization of this disorder reveals an essential role for ceruloplasmin in determining the rate of iron efflux from cells with mobilizable iron stores and provides new insights into the mechanisms of human iron metametabolism. Semin Hematol 39:282-289. Copyright 2002, Elsevier Science (USA). All rights reserved.

  • Biochemical analysis of a missense mutation in Aceruloplasminemia.
    The Journal of biological chemistry, 2001
    Co-Authors: Nathan E. Hellman, Satoshi Kono, Hiroaki Miyajima, Jonathan D. Gitlin
    Abstract:

    Aceruloplasminemia is an inherited neurodegenerative disease characterized by parenchymal iron accumulation secondary to loss-of-function mutations in the ceruloplasmin gene. To elucidate the molecular pathogenesis of Aceruloplasminemia, the biosynthesis of a missense mutant ceruloplasmin (P177R) occurring in an affected patient was examined. Chinese hamster ovary cells transfected with cDNAs encoding secreted and glycosylphosphatidylinositol (GPI)-linked wild-type or P177R human ceruloplasmin were examined by pulse-chase metabolic labeling. These experiments, as well as immunofluorescent analysis andN-linked glycosylation studies, indicate that both the secreted and GPI-linked forms of the P177R mutant are retained in the endoplasmic retireticulum (ER). The P177R mutation resides within a novel motif, which is repeated six times in human ceruloplasmin and is conserved in the homologous proteins hephaestin and factor VIII. Analysis of additional mutations in these motifs suggests a critical role for this region in ceruloplasmin trafficking and indicates that substitution of the arginine residue is critical to the ER retention of the P177R mutant. Metabolic labeling of transfected Chinese hamster ovary cells with 64Cu indicates that the P177R mutant is retained in the ER as an apoprotein and that copper is incorporated into both secreted and GPI-linked ceruloplasmin as a late event in the secretory pathway. Taken together, these studies reveal new insights into the determinants of holoceruloplasmin biosynthesis and indicate that Aceruloplasminemia can result from retention of mutant ceruloplasmin within the early secretory pathway.

  • targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux
    Proceedings of the National Academy of Sciences of the United States of America, 1999
    Co-Authors: Leah Z Harris, Alison P Durley, Tszkwong Man, Jonathan D. Gitlin
    Abstract:

    Aceruloplasminemia is an autosomal recessive disorder of iron metametabolism. Affected individuals evidence iron accumulation in tissue parenchyma in association with absent serum ceruloplasmin. Genetic studies of such patients reveal inherited mutations in the ceruloplasmin gene. To elucidate the role of ceruloplasmin in iron homeostasis, we created an animal model of Aceruloplasminemia by disrupting the murine ceruloplasmin (Cp) gene. Although normal at birth, Cp−/− mice demonstrate progressive accumulation of iron such that by one year of age all animals have a prominent elevation in serum ferritin and a 3- to 6-fold increase in the iron content of the liver and spleen. Histological analysis of affected tissues in these mice shows abundant iron stores within reticuloendothelial cells and hepatocytes. Ferrokinetic studies in Cp+/+ and Cp−/− mice reveal equivalent rates of iron absorption and plasma iron turnover, suggesting that iron accumulation results from altered compartmentalization within the iron cycle. Consistent with this concept, Cp−/− mice showed no abnormalities in cellular iron uptake but a striking impairment in the movement of iron out of reticuloendothelial cells and hepatocytes. Our findings reveal an essential physiologic role for ceruloplasmin in determining the rate of iron efflux from cells with mobilizable iron stores.

Satoshi Kono – One of the best experts on this subject based on the ideXlab platform.

  • Aceruloplasminemia with Abnormal Compound Heterozygous Mutations Developed Neurological Dysfunction during Phlebotomy Therapy.
    Internal medicine (Tokyo Japan), 2018
    Co-Authors: Maki Watanabe, Ken Ohyama, Masashi Suzuki, Yasunobu Nosaki, Takashi Hara, Katsushige Iwai, Satoshi Kono, Hiroaki Miyajima, Kenji Mokuno
    Abstract:

    Aceruloplasminemia is an autosomal recessive inherited disorder caused by ceruloplasmin gene mutations. The loss of ferroxidase activity of ceruloplasmin due to gene mutations causes a disturbance in cellular iron transport. We herein describe a patient with Aceruloplasminemia, who presented with diabetes mellitus that was treated by insulin injections, liver hemosiderosis treated by phlebotomy therapy, and neurological impairment. A genetic analysis of the ceruloplasmin gene revealed novel compound heterozygous mutations of c.1286_1290insTATAC in exon 7 and c.2185delC in exon 12. This abnormal compound heterozygote had typical clinical features similar to those observed in Aceruloplasminemia patients with other gene mutations.

  • chapter 45 Aceruloplasminemia
    Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (Fifth Edition), 2015
    Co-Authors: Satoshi Kono, Hiroaki Miyajima
    Abstract:

    Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis that is classified as an inherited neurodegenerative disorder called “neurodegeneration with brain iron accumulation” (NBIA). This disorder is caused by loss-of-function mutations encoding the ceruloplasmin gene. The clinical presentation involves hepatic iron overload, microscopic anemia, retinal degeneration, diabetes mellitus, and neurological symptoms, including cerebellar ataxia, involuntary movements and cognitive dysfunction. The diagnosis of Aceruloplasminemia is made based on the complete absence of serum ceruloplasmin, marked elevation of the ferritin concentration and abnormally low levels of intensity in the liver and brain, including the basal ganglia, thalamus, and dentate nucleus, on both T1- and T2-weighted magnetic resoresonanceging (MRI). Pathological and molecular biological investigations have revealed the pathogenesis of neurodegeneration to involve iron-mediated radical cellular injury resulting from marked accumulation of iron in the affected parenchymal tissues due to an iron efflux impairment caused by the absence of ferroxidase activity of ceruloplasmin.

  • Chapter 45 – Aceruloplasminemia
    Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease, 2015
    Co-Authors: Satoshi Kono, Hiroaki Miyajima
    Abstract:

    Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis that is classified as an inherited neurodegenerative disorder called “neurodegeneration with brain iron accumulation” (NBIA). This disorder is caused by loss-of-function mutations encoding the ceruloplasmin gene. The clinical presentation involves hepatic iron overload, microscopic anemia, retinal degeneration, diabetes mellitus, and neurological symptoms, including cerebellar ataxia, involuntary movements and cognitive dysfunction. The diagnosis of Aceruloplasminemia is made based on the complete absence of serum ceruloplasmin, marked elevation of the ferritin concentration and abnormally low levels of intensity in the liver and brain, including the basal ganglia, thalamus, and dentate nucleus, on both T1- and T2-weighted magnetic resonance imaging (MRI). Pathological and molecular biological investigations have revealed the pathogenesis of neurodegeneration to involve iron-mediated radical cellular injury resulting from marked accumulation of iron in the affected parenchymal tissues due to an iron efflux impairment caused by the absence of ferroxidase activity of ceruloplasmin.

Yoshitomo Takahashi – One of the best experts on this subject based on the ideXlab platform.

  • treatment of symptomatic heterozygous Aceruloplasminemia with oral zinc sulphate
    Brain & Development, 2007
    Co-Authors: Jens Kuhn, Hiroaki Miyajima, Yoshitomo Takahashi, H Bewermeyer, K F Kuhn, T U Hoogenraad
    Abstract:

    Aceruloplasminemia is an autosomal recessive and phenotypically primarily neurodegenerative disease caused by a homozygous mutation of the ceruloplasmin gene. The absence of ceruloplasmin and its ferroxidase activity leads to pathological iron overload in the brain and other organs. While heterozygous carriers of ceruloplasmin gene mutations have been believed to be asymptomatic, a number of cases with neurological deficits have recently been described. To date, an effective treatment has not been established for either Aceruloplasminemia or symptomatic heterozygous Aceruloplasminemia. The present report concerns the beneficial treatment of an 18-year-old girl with extrapyramidal and cerebellar-mediated movement disorder caused by a heterozygous mutation of the ceruloplasmin gene using oral zinc sulpsulphate.

  • Cys-881 is essential for the trafficking and secretion of truncated mutant ceruloplasmin in Aceruloplasminemia.
    Journal of hepatology, 2007
    Co-Authors: Satoshi Kono, Yoshitomo Takahashi, Hitoshi Suzuki, Kentaro Shirakawa, Toshiaki Oda, Masatoshi Kitagawa, Hiroaki Miyajima
    Abstract:

    Background/Aims Aceruloplasminemia is an inherited iron overload disorder caused by a mutation in the ceruloplasmin gene and characterized by iron accumulation in both the liver and brain. The aim of this study was to elucidate the molecular pathogenesis of Aceruloplasminemia by a functional analysis of mutant ceruloplasmin. Methods The effects of nonsense mutations including Y694ter, W858ter and R882ter were studied by the expression in cultured cells. Results A biogenesis study demonstrated that the Y694ter and W858ter mutants showed protein synthesis identical to that of wild type protein, however, the mutants were retained in the endoplasmic retireticulum (ER), while R882ter mutant was secreted out. Site-directed mutamutagenesis analyses suggested that Cys-881 was necessary for the secretion of the truncated ceruloplasmin. The W858ter mutant decreased viability in the transfected cells. The expression and the promoter activity of glucose-regulated protein 78 that is an ER stress sensor protein, were up-regulated in the transfected cells. Conclusions The truncated mutant containing Cys-881 was able to pass through the ER and was secreted, while the truncated mutant protein without Cys-881 appeared to accumulate in the ER thus leading to ER stress and eventually resulting in cell death.

  • Identification and in silico characterization of a novel compound heterozygosity associated with hereditary Aceruloplasminemia.
    Scandinavian journal of gastroenterology, 2007
    Co-Authors: Wolf Peter Hofmann, Hiroaki Miyajima, Yoshitomo Takahashi, Christoph Welsch, Ulrike Mihm, Christoph Krick, Stefan Zeuzem, Christoph Sarrazin
    Abstract:

    Background. Hereditary Aceruloplasminemia is an adult-onset autosomal recessive disease characterized by increased iron overload in the liver, pancreas, retina, and central nervous system. So far, 45 families with cases of Aceruloplasminemia have been reported world-wide and mainly missense and nonsense mutations in the ceruloplasmin gene were detected. Material and methods. Here, we report the identification, clinical characterization, and in silico analysis of a novel compound heterozygosity in the ceruloplasmin gene of a 31-year-old man with iron overload. Results. Increased serum ferritin levels, elevated iron saturation, as well as results of iron quantification in the liver and magnetic resoresonanceging-based measurement of T2 relaxation times of the substantia nigra consistently suggested iron overload. By sequencing the ceruloplasmin gene, so far unknown nucleotide replacements G229C, and C2131A were detected in exons 2 and 12, respectively. In silico analyses showed that the resulting amino acid