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

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  • Peter Huppke
  • Cornelia Brendel
  • Vera Kalscheuer
  • Georg Christoph Korenke
  • Iris Marquardt
  • Peter Freisinger
  • John Christodoulou
  • Merle Hillebrand
  • Gaele Pitelet
  • Callum Wilson
  • Ursula Gruber-Sedlmayr
  • Reinhard Ullmann
  • Stefan Haas
  • Orly Elpeleg
  • Gudrun Nürnberg
  • Peter Nürnberg
  • Shzeena Dad
  • Lisbeth Birk Møller
  • Stephen G Kaler
  • Jutta Gärtner
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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.
Original languageEnglish
JournalAmerican Journal of Human Genetics
Volume90
Issue number1
Pages (from-to)61-8
Number of pages8
ISSN0002-9297
DOIs
Publication statusPublished - 2012

    Research areas

  • Base Sequence, Cataract, Cerebellum, Ceruloplasmin, Child, Child, Preschool, Chromosome Mapping, Chromosomes, Human, Pair 3, Copper, Female, Hearing Loss, Hep G2 Cells, Humans, Infant, Male, Membrane Transport Proteins, Molecular Sequence Data, Mutation, Severity of Illness Index

ID: 36883564