title: Identification of the gene encoding the enzyme deficient in mucopolysaccharidosis IIIC (Sanfilippo disease type C).
abstract: Mucopolysaccharidosis IIIC (MPS IIIC), or Sanfilippo C, represents the only MPS disorder in which the responsible gene has not been identified; however, the gene has been localized to the pericentromeric region of chromosome 8. In an ongoing proteomics study of mouse lysosomal membrane proteins, we identified an unknown protein whose human homolog, TMEM76, was encoded by a gene that maps to 8p11.1. A full-length mouse expressed sequence tag was expressed in human MPS IIIC fibroblasts, and its protein product localized to the lysosome and corrected the enzymatic defect. The mouse sequence was used to identify the full-length human homolog (HGSNAT), which encodes a protein with no homology to other proteins of known function but is highly conserved among plants and bacteria. Mutational analyses of two MPS IIIC cell lines identified a splice-junction mutation that accounted for three mutant alleles, and a single base-pair insertion accounted for the fourth.
authors.affiliation: Research Institute, Metabolism Program, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.
authors.forename: Xiaolian
authors.initials: X
authors.lastname: Fan
authors.forename: Huiwen
authors.initials: H
authors.lastname: Zhang
authors.forename: Sunqu
authors.initials: S
authors.lastname: Zhang
authors.forename: Richard D
authors.initials: RD
authors.lastname: Bagshaw
authors.forename: Michael B
authors.initials: MB
authors.lastname: Tropak
authors.forename: John W
authors.initials: JW
authors.lastname: Callahan
authors.forename: Don J
authors.initials: DJ
authors.lastname: Mahuran
mesh_terms: D020413:3' Untranslated Regions; D000123:Acetyltransferases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D005091:Exons; D020224:Expressed Sequence Tags; D005347:Fibroblasts; D016368:Frameshift Mutation; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D007438:Introns; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009084:Mucopolysaccharidosis III / Q000201:enzymology / Q000235:genetics*; D011506:Proteins; D040901:Proteomics; D022821:RNA Splice Sites; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D011506:Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger; C018589:lysosomal proteins; D000123:Acetyltransferases; C514442:HGSNAT protein, human