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Zusammenfassung:
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 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 -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.
