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  Identification and in silico characterization of a novel compound heterozygosty associated with hereditary aceruloplasminemia

Hofmann, W. P., Welsch, C., Takahashi, Y., Miyajima, H., Mihm, U., Krick, C., et al. (2007). Identification and in silico characterization of a novel compound heterozygosty associated with hereditary aceruloplasminemia. Scandinavian Journal of Gastroenterology, 42(9), 1088-1094. doi:10.1080/00365520701278810.

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 Creators:
Hofmann, Wolf Peter, Author
Welsch, Christoph1, Author           
Takahashi, Yoshitomo, Author
Miyajima, Hiroaki, Author
Mihm, Ulrike, Author
Krick, Christoph, Author
Zeuzem, Stefan, Author
Sarrazin, Christoph, Author
Affiliations:
1Computational Biology and Applied Algorithmics, MPI for Informatics, Max Planck Society, ou_40046              

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 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. 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.

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Language(s): eng - English
 Dates: 2008-02-282007
 Publication Status: Issued
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 356571
DOI: 10.1080/00365520701278810
Other: Local-ID: C12573CC004A8E26-F677193A3AAE8DAEC12573EE004A1E79-HofmannWelsch2007
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Title: Scandinavian Journal of Gastroenterology
Source Genre: Journal
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Pages: - Volume / Issue: 42 (9) Sequence Number: - Start / End Page: 1088 - 1094 Identifier: ISSN: 0036-5521