Mutations in TMEM76* cause mucopolysaccharidosis IIIC (Sanfilippo C syndrome).
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.
Hrebícek
Martin
M
Institute for Inherited Metabolic Disorders, Charles University 1st School of Medicine, Prague, Czech Republic.
Mrázová
Lenka
L
Seyrantepe
Volkan
V
Durand
Stéphanie
S
Roslin
Nicole M
NM
Nosková
Lenka
L
Hartmannová
Hana
H
Ivánek
Robert
R
Cízkova
Alena
A
Poupetová
Helena
H
Sikora
Jakub
J
Urinovská
Jana
J
Stranecký
Viktor
V
Zeman
Jirí
J
Lepage
Pierre
P
Roquis
David
D
Verner
Andrei
A
Ausseil
Jérome
J
Beesley
Clare E
CE
Maire
Irène
I
Poorthuis
Ben J H M
BJ
van de Kamp
Jiddeke
J
van Diggelen
Otto P
OP
Wevers
Ron A
RA
Hudson
Thomas J
TJ
Fujiwara
T Mary
TM
Majewski
Jacek
J
Morgan
Kenneth
K
Kmoch
Stanislav
S
Pshezhetsky
Alexey V
AV
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
D018076:DNA, Complementary; D011993:Recombinant Fusion Proteins; D000123:Acetyltransferases; C514442:HGSNAT protein, human