Molecular basis of variant pseudo-hurler polydystrophy (mucolipidosis IIIC)

J Clin Invest. 2000 Mar;105(5):673-81. doi: 10.1172/JCI5826.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Chromosomes, Human, Pair 16
  • Cloning, Molecular
  • Female
  • Fibroblasts
  • Frameshift Mutation
  • Genetic Linkage
  • Humans
  • Lod Score
  • Lysosomes / enzymology
  • Lysosomes / metabolism*
  • Male
  • Molecular Sequence Data
  • Mucolipidoses / etiology
  • Mucolipidoses / genetics*
  • Pedigree
  • RNA, Messenger / metabolism
  • Sequence Analysis
  • Transferases (Other Substituted Phosphate Groups) / genetics*
  • Transferases (Other Substituted Phosphate Groups) / metabolism


  • RNA, Messenger
  • Transferases (Other Substituted Phosphate Groups)
  • UDP-N-acetylglucosamine-lysosomal-enzyme-N-acetylglucosaminephosphotransferase