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Loss of N-acetylglucosamine-1-phosphotransferase gamma subunit due to intronic mutation in GNPTG causes mucolipidosis type III gamma: Implications for molecular and cellular diagnostics.
Am J Med Genet A. 2010 Jan; 152A(1):124-32.AJ

Abstract

Mucolipidosis type III gamma (MLIII, pseudo-Hurler polydystrophy) is a rare autosomal recessive disorder where the activity of the multimeric GlcNAc-1-phosphotransferase is reduced and formation of the mannose 6-phosphate (M6P) recognition marker on lysosomal enzymes is impaired. In this disease, the targeting of lysosomal enzymes is affected resulting in their hypersecretion, and an intracellular deficiency of multiple hydrolases. We report the biochemical and molecular diagnosis of MLIII in three siblings, aged 17, 15, and 14 years, who presented with joint pain and progressive joint stiffness. In addition to missorting of newly synthesized lysosomal protease cathepsin D, there were low levels of M6P-containing proteins in cell extracts and media of cultured fibroblasts of the Patients. Direct sequencing identified a novel homozygous mutation in intron 7, IVS7-10G>A, of the GNPTG gene, which encodes the gamma-subunit of the GlcNAc-1-phosphotransferase. This mutation created a cryptic 3'-splice site resulting in a frameshift and premature translational termination (p.V176GfsX18). The GNPTG mRNA levels were markedly reduced in Patients' fibroblasts indicating that the intronic mutation mediates mRNA decay, which was confirmed by absence of the gamma-subunit protein. These data contribute to an efficient diagnostic strategy to identify Patients with MLIII gamma and characterize their biochemical defect in fibroblasts.

Authors+Show Affiliations

Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20034096

Citation

Pohl, Sandra, et al. "Loss of N-acetylglucosamine-1-phosphotransferase Gamma Subunit Due to Intronic Mutation in GNPTG Causes Mucolipidosis Type III Gamma: Implications for Molecular and Cellular Diagnostics." American Journal of Medical Genetics. Part A, vol. 152A, no. 1, 2010, pp. 124-32.
Pohl S, Encarnacão M, Castrichini M, et al. Loss of N-acetylglucosamine-1-phosphotransferase gamma subunit due to intronic mutation in GNPTG causes mucolipidosis type III gamma: Implications for molecular and cellular diagnostics. Am J Med Genet A. 2010;152A(1):124-32.
Pohl, S., Encarnacão, M., Castrichini, M., Müller-Loennies, S., Muschol, N., & Braulke, T. (2010). Loss of N-acetylglucosamine-1-phosphotransferase gamma subunit due to intronic mutation in GNPTG causes mucolipidosis type III gamma: Implications for molecular and cellular diagnostics. American Journal of Medical Genetics. Part A, 152A(1), 124-32. https://doi.org/10.1002/ajmg.a.33170
Pohl S, et al. Loss of N-acetylglucosamine-1-phosphotransferase Gamma Subunit Due to Intronic Mutation in GNPTG Causes Mucolipidosis Type III Gamma: Implications for Molecular and Cellular Diagnostics. Am J Med Genet A. 2010;152A(1):124-32. PubMed PMID: 20034096.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Loss of N-acetylglucosamine-1-phosphotransferase gamma subunit due to intronic mutation in GNPTG causes mucolipidosis type III gamma: Implications for molecular and cellular diagnostics. AU - Pohl,Sandra, AU - Encarnacão,Marisa, AU - Castrichini,Monica, AU - Müller-Loennies,Sven, AU - Muschol,Nicole, AU - Braulke,Thomas, PY - 2009/12/25/entrez PY - 2009/12/25/pubmed PY - 2010/4/7/medline SP - 124 EP - 32 JF - American journal of medical genetics. Part A JO - Am. J. Med. Genet. A VL - 152A IS - 1 N2 - Mucolipidosis type III gamma (MLIII, pseudo-Hurler polydystrophy) is a rare autosomal recessive disorder where the activity of the multimeric GlcNAc-1-phosphotransferase is reduced and formation of the mannose 6-phosphate (M6P) recognition marker on lysosomal enzymes is impaired. In this disease, the targeting of lysosomal enzymes is affected resulting in their hypersecretion, and an intracellular deficiency of multiple hydrolases. We report the biochemical and molecular diagnosis of MLIII in three siblings, aged 17, 15, and 14 years, who presented with joint pain and progressive joint stiffness. In addition to missorting of newly synthesized lysosomal protease cathepsin D, there were low levels of M6P-containing proteins in cell extracts and media of cultured fibroblasts of the Patients. Direct sequencing identified a novel homozygous mutation in intron 7, IVS7-10G>A, of the GNPTG gene, which encodes the gamma-subunit of the GlcNAc-1-phosphotransferase. This mutation created a cryptic 3'-splice site resulting in a frameshift and premature translational termination (p.V176GfsX18). The GNPTG mRNA levels were markedly reduced in Patients' fibroblasts indicating that the intronic mutation mediates mRNA decay, which was confirmed by absence of the gamma-subunit protein. These data contribute to an efficient diagnostic strategy to identify Patients with MLIII gamma and characterize their biochemical defect in fibroblasts. SN - 1552-4833 UR - https://www.unboundmedicine.com/medline/citation/20034096/Loss_of_N-acetylglucosamine-1-phosphotransferase_gamma_subunit_due_to_intronic_mutation_in_GNPTG_causes_mucolipidosis_type_III_gamma:_Implications_for_molecular_and_cellular_diagnostics L2 - https://doi.org/10.1002/ajmg.a.33170 DB - PRIME DP - Unbound Medicine ER -