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The role of the scoring system for the diagnosis of Wilson's ...

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The role of the scoring system for the diagnosis of Wilson's ...

  1. 1. ATP7B mutation in patients with Wilson disease<br />Seoul National University Children’s Hospital<br />Gastroenterology, hepatology and Nutrion<br /> F. Sang hee, Cho <br />
  2. 2. Wilson disease (WD) was first described in 1912 by Kinnear Wilson as “progressive lenticular degeneration,” a familial, lethal neurological disease accompanied by chronic liver disease leading to cirrhosis.<br />In 1993, the abnormal gene in WD was identified. ATP7B encodes a metal-transporting P-type adenosine triphosphatase (ATPase)<br />Introduction<br />
  3. 3. Copper Homeostasis<br />Critical role in human metabolism as a cofactor of key metabolic enzymes, which are involved in respiration, neurotransmitter biosynthesis, radical detoxification, iron metabolism, and many other physiological processes<br />Average daily intake of copper : 1-3mg<br />When intake is less than 1mg/day, more than 50% of the copper is absorbed, when copper intake is more than 5mg/day, less than 20% is absorbed<br />Liver is the principal storage site for copper and regulates its excretion into the bile<br />
  4. 4. Copper transporters<br />High-affinity copper transporter (Ctr1) : polytopic membrane protein involved in the copper uptake at the hepatocyte plasma membrane<br />Metallothioneins (MT) : a group of cysteine-rich intracellular proteins capable of binding metal ions<br />Metallochaperones (ATOX1/HAH1, CCS, Cox17) : involved in the transfer of copper to specific cellular targets<br />Cu-ATPase : ATP7B, ATP7A<br />P. Ferenci et al.Pathophysiology and clinical features of Wilson disease 2004;19:229-39<br />
  5. 5. Copper transporters<br />ATPase 7A (ATP7A)<br />In intestine, choroid plexus, vascular smooth muscle, adrenal gland<br />ATPase 7B (ATP7B)<br />primarily expressed in the liver, and also in the brain, kidney, placenta.<br />membrane protein located in the trans-Golgi involved in incorporation of free copper into apoceruloplasminand in transporting the excess copper to secretory vesicles for excretion into biliarycanaliculi.<br />
  6. 6. Svetlana et.al. Function and Regulation of Human Copper-Transporting ATPase.Physiol Rev 2007;87:1011-46<br />
  7. 7. Intracellular pathways of copper distribution<br />NML45<br />Svetlana et.al. Function and Regulation of Human Copper-Transporting ATPase.Physiol Rev 2007;87:1011-46<br />
  8. 8. Localization and function of Cu-ATPases<br />Svetlana et.al. Function and Regulation of Human Copper-Transporting ATPase.Physiol Rev 2007;87:1011-46<br />
  9. 9. Gereral Architecture of Cu-ATPases<br />Six N-terminal metal-binding sites (MBS)<br />Actuator domain (A-domain)<br />Phosphorylation domain(amino acid residues 971-1035;containing the highly conserved Asp-Lys-Thr-Gly-Thr motif)<br />Nucleotide-binding domain(N-domain; amino acid residues 1240-1291)<br />Eight hydrophobic transmembrane sequences<br />Svetlana et.al. Function and Regulation of Human Copper-Transporting ATPase.Physiol Rev 2007;87:1011-46<br />
  10. 10. GereralATPase catalytic cycle<br />de Bie, P et al. J Med Genet 2007;44:673-688<br />
  11. 11. Structure of isolated NH2-terminal metal-binding domain(MBD)<br />Svetlana et.al. Function and Regulation of Human Copper-Transporting ATPase.Physiol Rev 2007;87:1011-46<br />
  12. 12. ATP-binding domain of ATP7B<br />Sites of Wilson disease-causing mutations are in red.<br />The bound ATP molecule is in green.<br />Svetlana et.al. Function and Regulation of Human Copper-Transporting ATPase.Physiol Rev 2007;87:1011-46<br />
  13. 13. WD gene showing the site of common mutations<br />At least 300 distinct mutations : missence, nonsense, deletions, insertion<br />Peter F. Regional distribution of mutations of the ATP7B gene. Hum Genet 2006;120:151-59<br />
  14. 14. Genotype-to-phenotype correlations in WD <br />Genotype-to-phenotype correlations in WD are hampered by the high prevalence of compound heterozygotes and the relative paucity of homozygotes.<br />Studies in homozygotes suggest that mutations affecting critical portions of the protein, including copper-binding domains or the ATPase loop, may lead to early onset of hepatic disease, but strict concordance is difficult to prove.<br />In general, convincing genotype-phenotype correlations remain elusive.<br />
  15. 15. In the genetically confirmed 92 WD patients,<br />Common mutations (allele frequency)<br />R778L (40%), <br />A874V and N1270S (8.7%)<br />L1083F and V872X (6.0%) <br />Fourteen (15%) WD patients were homozygous and 46(50%) heterozygous for the R778L.<br />Mutation analysis of ATP7B in 114 WD patients (SNUCH 2009)<br />
  16. 16. Clinical and laboratory data of 92 WD patients and correlation with R778L<br />1) ANOVA<br />2) Chi-square test <br />
  17. 17. THANK YOU~~!!!<br />
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  21. 21. THANK YOU~~!!!<br />

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