title: Identification and in silico characterization of a novel compound heterozygosity associated with hereditary aceruloplasminemia.
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.
  
  
  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 resonance imaging-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 changes Asp58His and Gln692Lys are located at highly conserved positions. The Asp58His mutation is located on the surface of the protein, alters polarity, and may interfere with copper incorporation or ceruloplasmin trafficking. The Gln692Lys mutation is mapped to a beta-strand of domain 4 and may lead to conformational change of the cupredoxin fold.
  
  
  CONCLUSIONS
  As causative for aceruloplasminemia, a formerly unknown compound heterozygosity in the ceruloplasmin gene was identified. In silico characterization suggests an impact on ceruloplasmin conformation and function.
authors: Klinik für Innere Medizin II, Kirrbergerstrasse, Universitätsklinikum des Saarlandes, Homburg, Germany.
authors: Wolf Peter
authors: WP
authors: Hofmann
authors: Christoph
authors: C
authors: Welsch
authors: Yoshitomo
authors: Y
authors: Takahashi
authors: Hiroaki
authors: H
authors: Miyajima
authors: Ulrike
authors: U
authors: Mihm
authors: Christoph
authors: C
authors: Krick
authors: Stefan
authors: S
authors: Zeuzem
authors: Christoph
authors: C
authors: Sarrazin
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology; D002570:Ceruloplasmin / Q000172:deficiency* / Q000235:genetics*; D003300:Copper / Q000378:metabolism; D005293:Ferritins / Q000097:blood; D006801:Humans; D019190:Iron Overload / Q000175:diagnosis / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000235:genetics; D017354:Point Mutation / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D003300:Copper; D005293:Ferritins; D002570:Ceruloplasmin