title: Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss, and low serum copper and ceruloplasmin.
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.
authors.affiliation: Department of Pediatrics and Pediatric Neurology, Georg August University, Göttingen, Germany. phuppke@med.uni-goettingen.de
authors.forename: Peter
authors.initials: P
authors.lastname: Huppke
authors.forename: Cornelia
authors.initials: C
authors.lastname: Brendel
authors.forename: Vera
authors.initials: V
authors.lastname: Kalscheuer
authors.forename: Georg Christoph
authors.initials: GC
authors.lastname: Korenke
authors.forename: Iris
authors.initials: I
authors.lastname: Marquardt
authors.forename: Peter
authors.initials: P
authors.lastname: Freisinger
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.forename: Merle
authors.initials: M
authors.lastname: Hillebrand
authors.forename: Gaele
authors.initials: G
authors.lastname: Pitelet
authors.forename: Callum
authors.initials: C
authors.lastname: Wilson
authors.forename: Ursula
authors.initials: U
authors.lastname: Gruber-Sedlmayr
authors.forename: Reinhard
authors.initials: R
authors.lastname: Ullmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Haas
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Shzeena
authors.initials: S
authors.lastname: Dad
authors.forename: Lisbeth Birk
authors.initials: LB
authors.lastname: Møller
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Kaler
authors.forename: Jutta
authors.initials: J
authors.lastname: Gärtner
mesh_terms: D001483:Base Sequence; D002386:Cataract / Q000151:congenital / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities / Q000254:growth & development; D002570:Ceruloplasmin / Q000032:analysis / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D003300:Copper / Q000097:blood*; D005260:Female; D034381:Hearing Loss / Q000151:congenital / Q000235:genetics*; D056945:Hep G2 Cells; D006801:Humans; D007223:Infant; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D026901:Membrane Transport Proteins; C484549:SLC33A1 protein, human; D003300:Copper; D002570:Ceruloplasmin