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SHR Neuro Cancer Cardio Lipid Metab Microb
Huppke, P; Brendel, C; Kalscheuer, V; Korenke, GC; Marquardt, I; Freisinger, P; Christodoulou, J; Hillebrand, M; Pitelet, G; Wilson, C; Gruber-Sedlmayr, U; Ullmann, R; Haas, S; Elpeleg, O; Nürnberg, G; Nürnberg, P; Dad, S; Mller, LB; Kaler, SG; Gärtner, J.
Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss, and low serum copper and ceruloplasmin.
AM J HUM GENET. 2012; 90(1): 61-68.
Doi: 10.1016/j.ajhg.2011.11.030
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- 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.
Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. - Find related publications in this database (using NLM MeSH Indexing)
- Base Sequence -
- Cataract - congenital
- Cerebellum - abnormalities
- Ceruloplasmin - analysis
- Child -
- Child, Preschool -
- Chromosome Mapping -
- Chromosomes, Human, Pair 3 - genetics
- Copper - blood
- Female -
- Hearing Loss - congenital
- Hep G2 Cells -
- Humans -
- Infant -
- Male -
- Membrane Transport Proteins - biosynthesis
- Molecular Sequence Data -
- Mutation - genetics
- Severity of Illness Index -