title: Aberrant expression of copper associated genes after copper accumulation in COMMD1-deficient dogs.
abstract: BACKGROUND
  COMMD1-deficient dogs progressively develop copper-induced chronic hepatitis. Since high copper leads to oxidative damage, we measured copper metabolism and oxidative stress related gene products during development of the disease.
  
  
  METHODS
  Five COMMD1-deficient dogs were studied from 6 months of age over a period of five years. Every 6 months blood was analysed and liver biopsies were taken for routine histological evaluation (grading of hepatitis), rubeanic acid copper staining and quantitative copper analysis. Expression of genes involved in copper metabolism (COX17, CCS, ATOX1, MT1A, CP, ATP7A, ATP7B, ) and oxidative stress (SOD1, catalase, GPX1 ) was measured by qPCR. Due to a sudden death of two animals, the remaining three dogs were treated with d-penicillamine from 43 months of age till the end of the study. Presented data for time points 48, 54, and 60 months was descriptive only.
  
  
  RESULTS
  A progressive trend from slight to marked hepatitis was observed at histology, which was clearly preceded by an increase in semi-quantitative copper levels starting at 12 months until 42 months of age. During the progression of hepatitis most gene products measured were transiently increased. Most prominent was the rapid increase in the copper binding gene product MT1A mRNA levels. This was followed by a transient increase in ATP7A and ATP7B mRNA levels.
  
  
  CONCLUSIONS
  In the sequence of events, copper accumulation induced progressive hepatitis followed by a transient increase in gene products associated with intracellular copper trafficking and temporal activation of anti-oxidative stress mechanisms.
authors: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, P.O. Box 80154, 3508 TD, Utrecht, The Netherlands. Electronic address: r.p.favier@uu.nl.
authors: Robert P
authors: RP
authors: Favier
authors: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, P.O. Box 80154, 3508 TD, Utrecht, The Netherlands.
authors: Bart
authors: B
authors: Spee
authors: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, P.O. Box 80154, 3508 TD, Utrecht, The Netherlands.
authors: Hille
authors: H
authors: Fieten
authors: TCCI Consultancy BV, The Netherlands.
authors: Ted S G A M
authors: TS
authors: van den Ingh
authors: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, P.O. Box 80154, 3508 TD, Utrecht, The Netherlands.
authors: Baukje A
authors: BA
authors: Schotanus
authors: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, P.O. Box 80154, 3508 TD, Utrecht, The Netherlands.
authors: Bas
authors: B
authors: Brinkhof
authors: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, P.O. Box 80154, 3508 TD, Utrecht, The Netherlands.
authors: Jan
authors: J
authors: Rothuizen
authors: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, P.O. Box 80154, 3508 TD, Utrecht, The Netherlands.
authors: Louis C
authors: LC
authors: Penning
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D004285:Dogs; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006505:Hepatitis / Q000097:blood / Q000473:pathology; D008297:Male
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001647:Bile Acids and Salts; D027682:Cation Transport Proteins; D003300:Copper; D000410:Alanine Transaminase
keywords: COMMD1-deficient dogs; Copper accumulation; Translational research