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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.
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Molecular basis of variant pseudo-Hurler polydystrophy (mucolipidosis IIIC)

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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

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Figure 5

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Sequence analysis of the mutant and wild-type γ-subunit cDNA. RNA was is...
Sequence analysis of the mutant and wild-type γ-subunit cDNA. RNA was isolated from cultured fibroblasts, reverse transcribed, and a 300-bp portion of the γ-subunit cDNA amplified by PCR as described in Methods. The amplified fragment was resolved by agarose gel electrophoresis, excised, and directly sequenced using the PCR primers as primers and fluorescent terminators. (a) Wild-type sequence. (b) Mutant sequence. (c) Effect of the insertion on the γ-subunit protein.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 11 patents
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