Identification and in silico characterization of a novel compound heterozygosity associated with hereditary aceruloplasminemia.
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.
Hofmann
Wolf Peter
WP
Klinik für Innere Medizin II, Kirrbergerstrasse, Universitätsklinikum des Saarlandes, Homburg, Germany.
Welsch
Christoph
C
Takahashi
Yoshitomo
Y
Miyajima
Hiroaki
H
Mihm
Ulrike
U
Krick
Christoph
C
Zeuzem
Stefan
S
Sarrazin
Christoph
C
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
D003300:Copper; D005293:Ferritins; D002570:Ceruloplasmin