title: Molecular basis of variant pseudo-hurler polydystrophy (mucolipidosis IIIC)
abstract: Mucolipidosis IIIC, or variant pseudo-Hurler polydystrophy, is an autosomal recessive disease of lysosomal hydrolase trafficking. Unlike the related diseases, mucolipidosis II and IIIA, the enzyme affected in mucolipidosis IIIC (N-Acetylglucosamine-1-phosphotransferase [GlcNAc-phosphotransferase]) retains full transferase activity on synthetic substrates but lacks activity on lysosomal hydrolases. Bovine GlcNAc-phosphotransferase has recently been isolated as a multisubunit enzyme with the subunit structure alpha(2)beta(2)gamma(2). We cloned the cDNA for the human gamma-subunit and localized its gene to chromosome 16p. We also showed, in a large multiplex Druze family that exhibits this disorder, that MLIIIC also maps to this chromosomal region. Sequence analysis of the gamma-subunit cDNA in patients from 3 families identified a frameshift mutation, in codon 167 of the gamma subunit, that segregated with the disease, indicating MLIIIC results from mutations in the phosphotransferase gamma-subunit gene. This is to our knowledge the first description of the molecular basis for a human mucolipidosis and suggests that the gamma subunit functions in lysosomal hydrolase recognition.
authors.affiliation: Department of Human Genetics, Hadassah Hebrew University Hospital, Jerusalem 91120, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Raas-Rothschild
authors.forename: V
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: M
authors.initials: M
authors.lastname: Bao
authors.forename: E
authors.initials: E
authors.lastname: Genin
authors.forename: R
authors.initials: R
authors.lastname: Salomon
authors.forename: K
authors.initials: K
authors.lastname: Brewer
authors.forename: M
authors.initials: M
authors.lastname: Zeigler
authors.forename: H
authors.initials: H
authors.lastname: Mandel
authors.forename: S
authors.initials: S
authors.lastname: Toth
authors.forename: B
authors.initials: B
authors.lastname: Roe
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: W M
authors.initials: WM
authors.lastname: Canfield
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002885:Chromosomes, Human, Pair 16; D003001:Cloning, Molecular; D005260:Female; D005347:Fibroblasts; D016368:Frameshift Mutation; D008040:Genetic Linkage; D006801:Humans; D008126:Lod Score; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009081:Mucolipidoses / Q000209:etiology / Q000235:genetics*; D010375:Pedigree; D012333:RNA, Messenger / Q000378:metabolism; D017421:Sequence Analysis; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D017855:Transferases (Other Substituted Phosphate Groups); C030012:UDP-N-acetylglucosamine-lysosomal-enzyme-N-acetylglucosaminephosphotransferase