Molecular basis of variant pseudo-Hurler polydystrophy (mucolipidosis IIIC)
Annick Raas-Rothschild, … , Arnold Munnich, William M. Canfield
Annick Raas-Rothschild, … , Arnold Munnich, William M. Canfield
Published March 1, 2000
Citation Information: J Clin Invest. 2000;105(5):673-681. https://doi.org/10.1172/JCI5826.
View: Text | PDF
Article

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 α2β2γ2. We cloned the cDNA for the human γ-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 γ-subunit cDNA in patients from 3 families identified a frameshift mutation, in codon 167 of the γ subunit, that segregated with the disease, indicating MLIIIC results from mutations in the phosphotransferase γ-subunit gene. This is to our knowledge the first description of the molecular basis for a human mucolipidosis and suggests that the γ subunit functions in lysosomal hydrolase recognition.

Authors

Annick Raas-Rothschild, Valerie Cormier-Daire, Ming Bao, Emmanuelle Genin, Remi Salomon, Kevin Brewer, Marsha Zeigler, Hanna Mandel, Steve Toth, Bruce Roe, Arnold Munnich, William M. Canfield

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
(a) Nucleotide and deduced amino acid sequence of the human GlcNAc-phosp...
(a) Nucleotide and deduced amino acid sequence of the human GlcNAc-phosphotransferase γ-subunit cDNA. The predicted protein sequence is shown below the DNA sequence. The putative signal peptide is indicated by the dotted underline. Sequences homologous to the bovine γ subunit are indicated by single underline. Two potential sites for N-linked glycosylation are indicated by double underline. (b) Northern blot analysis of GlcNAc-phosphotransferase γ subunit. The γ-subunit cDNA was random labeled and hybridized to a human multiple tissue Northern blot (CLONTECH); each lane contained 2 μg of poly(A)+ RNA from the indicated tissue. The filter was washed at 65°C in 0.1 × SSC, 0.1% SDS, and exposed for 18 hours. In a, transcripts of 1.3 kb are identified in all tissues with additional larger transcripts identified in lung; in b, after hybridization, the blot was stripped and rehybridized with a probe for human β-actin mRNA as a control for loading.