title: Mutations in TMEM76* cause mucopolysaccharidosis IIIC (Sanfilippo C syndrome).
abstract: Mucopolysaccharidosis IIIC (MPS IIIC, or Sanfilippo C syndrome) is a lysosomal storage disorder caused by the inherited deficiency of the lysosomal membrane enzyme acetyl-coenzyme A: alpha -glucosaminide N-acetyltransferase (N-acetyltransferase), which leads to impaired degradation of heparan sulfate. We report the narrowing of the candidate region to a 2.6-cM interval between D8S1051 and D8S1831 and the identification of the transmembrane protein 76 gene (TMEM76), which encodes a 73-kDa protein with predicted multiple transmembrane domains and glycosylation sites, as the gene that causes MPS IIIC when it is mutated. Four nonsense mutations, 3 frameshift mutations due to deletions or a duplication, 6 splice-site mutations, and 14 missense mutations were identified among 30 probands with MPS IIIC. Functional expression of human TMEM76 and the mouse ortholog demonstrates that it is the gene that encodes the lysosomal N-acetyltransferase and suggests that this enzyme belongs to a new structural class of proteins that transport the activated acetyl residues across the cell membrane.
authors.affiliation: Institute for Inherited Metabolic Disorders, Charles University 1st School of Medicine, Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrebícek
authors.forename: Lenka
authors.initials: L
authors.lastname: Mrázová
authors.forename: Volkan
authors.initials: V
authors.lastname: Seyrantepe
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Durand
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Roslin
authors.forename: Lenka
authors.initials: L
authors.lastname: Nosková
authors.forename: Hana
authors.initials: H
authors.lastname: Hartmannová
authors.forename: Robert
authors.initials: R
authors.lastname: Ivánek
authors.forename: Alena
authors.initials: A
authors.lastname: Cízkova
authors.forename: Helena
authors.initials: H
authors.lastname: Poupetová
authors.forename: Jakub
authors.initials: J
authors.lastname: Sikora
authors.forename: Jana
authors.initials: J
authors.lastname: Urinovská
authors.forename: Viktor
authors.initials: V
authors.lastname: Stranecký
authors.forename: Jirí
authors.initials: J
authors.lastname: Zeman
authors.forename: Pierre
authors.initials: P
authors.lastname: Lepage
authors.forename: David
authors.initials: D
authors.lastname: Roquis
authors.forename: Andrei
authors.initials: A
authors.lastname: Verner
authors.forename: Jérome
authors.initials: J
authors.lastname: Ausseil
authors.forename: Clare E
authors.initials: CE
authors.lastname: Beesley
authors.forename: Irène
authors.initials: I
authors.lastname: Maire
authors.forename: Ben J H M
authors.initials: BJ
authors.lastname: Poorthuis
authors.forename: Jiddeke
authors.initials: J
authors.lastname: van de Kamp
authors.forename: Otto P
authors.initials: OP
authors.lastname: van Diggelen
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudson
authors.forename: T Mary
authors.initials: TM
authors.lastname: Fujiwara
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Kenneth
authors.initials: K
authors.lastname: Morgan
authors.forename: Stanislav
authors.initials: S
authors.lastname: Kmoch
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Pshezhetsky
mesh_terms: D000123:Acetyltransferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009084:Mucopolysaccharidosis III / Q000201:enzymology* / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D011993:Recombinant Fusion Proteins; D000123:Acetyltransferases; C514442:HGSNAT protein, human