A splicing mutation in the ?/? GlcNAc-1-phosphotransferase gene results in an adult onset form of mucolipidosis III associated with sensory neuropathy and cardiomyopathy

Washington University in St. Louis, San Luis, Missouri, United States
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 02/2005; 132(4):369-75. DOI: 10.1002/ajmg.a.30498
Source: PubMed


A 47-year-old female who presented with a dilated cardiomyopathy and mild neuropathy was found to have pseudoHurler polydystrophy (mucolipidosis III). The serum lysosomal enzymes were strikingly elevated and GlcNAc-1-phosphotransferase activity in the patient's fibroblasts was 3% of normal. Sequence analysis of the patient's genomic DNA revealed a homozygous mutation of the last nucleotide of the 135-bp exon 7 of the phosphotransferase gene encoding the alpha/beta subunits, resulting in aberrant splicing and skipping of this exon. Remarkably, none of the skeletal and connective tissue anomalies characteristic of the disease were present. This case is the first example of mucolipidosis III presenting in an adult patient and further broadens the clinical spectrum of the disease.

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Available from: Beat Steinmann, Jun 27, 2014
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    • ", the first encoding the α-and β-subunits and the other the γ-subunit (Little et al., 1986; Bao et al., 1996; Kornfeld et al., 1999; Raas- Rothschild et al., 2000, 2004). Molecular lesions in the γ-subunit appear to be the main reason for the onset of pathogenesis in ML III patients (Raas-Rothschild et al., 2000, 2004; Steet et al., 2005). These mutations are presumed to alter the structure of the multisubunit complex resulting in reduced but significant levels of N-acetylglucosamine 1-phosphotransferase activity. "
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    ABSTRACT: The lysosomal storage disorders (LSD), I-cell disease (mucolipidosis type II, ML II), and mucolipidosis type III (ML III) represent the severe and attenuated phenotypes resulting from the dysfunction of N-acetylglucosamine 1-phosphotransferase. Like other LSD, these disorders can present with a spectrum of clinical phenotypes. However, unlike other LSD these two disorders are genetically distinct, affecting different gene products (subunits) of the same N-acetylglucosamine 1-phosphotransferase enzyme. This chapter gives a brief overview of the disorder, how it has been diagnosed, together with the molecular cause and its impact on lysosomal biogenesis. Potential treatment strategies for patients with I-cell disease are also discussed.
    Lysosomal Storage Disorders, Edited by J. Barranger ed, 01/2007: chapter I-cell Disease; Springer, CRC Press, Boca Raton, Florida USA.
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    • "The results of these studies allowed us to demonstrate that these diseases are allelic, to define the molecular basis of these diseases, and to propose molecular criteria to distinguish them. One of us (M.K.) recently reported a mutation in GNPTAB in a patient with MLIIIA (Steet et al. 2005) that is not included here. Part of the work of the present study was presented at the Joint Meeting of the Society for Glycobiology and the Japanese Society of Carbohydrate Research (Kudo et al. 2004). "
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    ABSTRACT: Fibroblasts or lymphoblasts were derived from subjects with clinically diagnosed MLII and MLIII. Clinical information is shown in table 1. Cell lines from pedigrees GM03066, GM00080, GM00081, GM02013, GM02014, GM02274, GM02687, GM02660, GM01586, GM01589, GM01590, GM02046, GM02047, GM02273, GM02558, GM02559, GM01494, GM07255, GM07256, GM00113, GM01759, GM02065, GM02425, GM03112, GM03685, and GM03392 that have mucolipidosis, as well as normal human fibroblast line GM05565, were obtained from the National Institute of General Medical Sciences (NIGMS) Human Genetic Cells Repository at the Coriell Institute for Medical Research (Camden, NJ). Cell line F1515 was a kind gift from Dr. A. Raas-Rothschild (Hadassah University Hospital, Israel). Cell line F2954 was obtained from Dr. Miko Stewart (Children's Memorial Hospital, Chicago). Cell lines GM1006 (LT) and C.M. were obtained from Dr. Thomas B. Shows (Roswell Park Cancer Institute, Buffalo, NY). Cell line R.S. was obtained from Dr. Catherine M. Bollard (Texas Children's Hospital, Houston). Two of the MLII cell lines (GM02273 and GM03112) could not be recovered after freezing. It is well known that fibroblasts from patients with mucolipidosis are frequently difficult to recover after freezing. This work was performed with the approval of the Institutional Research Board of the University of Oklahoma Health Sciences Center. Although it is not current standard practice, patient initials have been used in some cases, to allow comparison with previously published results.
    The American Journal of Human Genetics 04/2006; 78(3):451-63. DOI:10.1086/500849 · 10.93 Impact Factor
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    ABSTRACT: Mucolipidosis type III (ML III, pseudo-Hurler polydystrophy), an autosomal recessive inherited disorder of lysosomal enzyme targeting is due to a defective N-acetylglucosamine 1-phosphotransferase (phosphotransferase) activity and leads to the impaired formation of mannose 6-phosphate markers in soluble lysosomal enzymes followed by their increased excretion into the serum. Mutations in the phosphotransferase gamma subunit gene (GNPTAG) have been reported to be responsible for ML III. Here we report on a 14-year-old adolescent with a mild clinical phenotype of ML III. He presented with progressive joint stiffness and swelling. Urinary oligosaccharide and mucopolysaccharide excretion was normal. Lysosomal enzyme activities were significantly elevated in the serum and decreased in cultured fibroblasts. Impaired trafficking of the lysosomal protease cathepsin D (CtsD) was confirmed by metabolic labeling of the patient's fibroblasts. Neither mutations in the GNPTAG gene nor alterations in the GNPTAG mRNA level were detected whereas the steady state concentration of the 97 kDa GNPTAG dimer was reduced. Most importantly, the patient is homozygous for a pathogenic nucleotide substitution and a polymorphism in the phosphotransferase alpha/beta subunit gene (GNPTA). The data indicate that defects in genes other than GNPTAG can be linked to ML III contributing to the variability of the phenotype.
    American Journal of Medical Genetics Part A 09/2005; 137A(3):235-40. DOI:10.1002/ajmg.a.30868 · 2.16 Impact Factor
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