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  Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss, and low serum copper and ceruloplasmin

Huppke, P., Brendel, C., Kalscheuer, V., Korenke, G. C., Marquardt, I., Freisinger, P., et al. (2012). Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss, and low serum copper and ceruloplasmin. The American Journal of Human Genetics, 90(1), 61-8. doi:10.1016/j.ajhg.2011.11.030.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-E87A-F Version Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-E87B-D
Genre: Journal Article

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 Creators:
Huppke, P., Author
Brendel, C., Author
Kalscheuer, V.1, Author              
Korenke, G. C., Author
Marquardt, I., Author
Freisinger, P., Author
Christodoulou, J., Author
Hillebrand, M., Author
Pitelet, G., Author
Wilson, C., Author
Gruber-Sedlmayr, U., Author
Ullmann, R.2, Author              
Haas, S.3, Author              
Elpeleg, O., Author
Nürnberg, G., Author
Nürnberg, P., Author
Dad, S., Author
Møller, L. B., Author
Kaler, S. G., Author
Gärtner, J., Author
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, Berlin, Germany, ou_1479642              
2Molecular Cytogenetics (Reinhard Ullmann), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, Berlin, Germany, ou_1479645              
3Gene Structure and Array Design (Stefan Haas), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, Berlin, Germany, ou_1479640              

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Free keywords: Base Sequence Cataract/congenital/*genetics Cerebellum/abnormalities/growth & development Ceruloplasmin/analysis/*metabolism/secretion Child Child, Preschool Chromosome Mapping Chromosomes, Human, Pair 3/genetics Copper/*blood Female Hearing Loss/congenital/*genetics Hep G2 Cells Humans Infant Male Membrane Transport Proteins/biosynthesis/*genetics Molecular Sequence Data Mutation/*genetics Severity of Illness Index
 Abstract: Low copper and ceruloplasmin in serum are the diagnostic hallmarks for Menkes disease, Wilson disease, and aceruloplasminemia. We report on five patients from four unrelated families with these biochemical findings who presented with a lethal autosomal-recessive syndrome of congenital cataracts, hearing loss, and severe developmental delay. Cerebral MRI showed pronounced cerebellar hypoplasia and hypomyelination. Homozygosity mapping was performed and displayed a region of commonality among three families at chromosome 3q25. Deep sequencing and conventional sequencing disclosed homozygous or compound heterozygous mutations for all affected subjects in SLC33A1 encoding a highly conserved acetylCoA transporter (AT-1) required for acetylation of multiple gangliosides and glycoproteins. The mutations were found to cause reduced or absent AT-1 expression and abnormal intracellular localization of the protein. We also showed that AT-1 knockdown in HepG2 cells leads to reduced ceruloplasmin secretion, indicating that the low copper in serum is due to reduced ceruloplasmin levels and is not a sign of copper deficiency. The severity of the phenotype implies an essential role of AT-1 in proper posttranslational modification of numerous proteins, without which normal lens and brain development is interrupted. Furthermore, AT-1 defects are a new and important differential diagnosis in patients with low copper and ceruloplasmin in serum.

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Language(s): eng - English
 Dates: 2012-01-13
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.ajhg.2011.11.030
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Title: The American Journal of Human Genetics
  Other : Am. J. Hum. Genet.
Source Genre: Journal
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Publ. Info: American Society of Human Genetics
Pages: - Volume / Issue: 90 (1) Sequence Number: - Start / End Page: 61 - 8 Identifier: ISSN: 0002-9297
CoNE: /journals/resource/954925377893_1