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Thomas Braulke - One of the best experts on this subject based on the ideXlab platform.
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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.
American Journal of Medical Genetics Part A, 2009Co-Authors: Sandra Pohl, Nicole Muschol, Marisa Encarnacão, Monica Castrichini, Sven Müller-loennies, Thomas BraulkeAbstract: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.
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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.
American Journal of Medical Genetics Part A, 2009Co-Authors: Sandra Pohl, Nicole Muschol, Marisa Encarnacão, Monica Castrichini, Sven Müller-loennies, Thomas BraulkeAbstract: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 γ-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 γ-subunit protein. These data contribute to an efficient diagnostic strategy to identify Patients with MLIII gamma and characterize their biochemical defect in fibroblasts. © 2009 Wiley-Liss, Inc.
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Missense mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTA) in a patient with mucolipidosis II induces changes in the size and cellular distribution of GNPTG.
Human Mutation, 2006Co-Authors: Stephan Tiede, Michael Cantz, Jürgen W. Spranger, Thomas BraulkeAbstract:Mucolipidosis type II (ML II; I-cell disease) and mucolipidosis III (ML III; pseudo Hurler Polydystrophy) are autosomal recessively inherited disorders caused by a defective N-acetylglucosamine 1-phosphotransferase (phosphotransferase). The formation of mannose 6-phosphate markers in soluble lysosomal enzymes is impeded leading to their increased excretion into the serum, to cellular deficiency of multiple hydrolases, and lysosomal storage of non-digested material. Phosphotransferase deficiency is caused by mutations in GNPTA and GNPTG encoding phosphotransferase subunits. Here we report on an adolescent with progressive joint contractions and other signs of mucolipidosis II who survived to the age of 14 years. Impaired trafficking of lysosomal enzymes cathepsin D and -hexosaminidase in metabolically labeled fibroblasts was documented. Mutations in the GNPTG gene and alterations in the GNPTG mRNA level were not detected. A different electrophoretic mobility of the 97 kDa GNPTG dimer suggested posttranslational modification abrogating the compartmentalization of GNPTG in the Golgi apparatus. A nucleotide substitution in the GNPTA gene (c.3707A>T) was identified altering the predicted C-terminal transmembrane anchor of the phosphotransferase subunit. The data demonstrate that defective GNPTA not only impairs lysosomal enzyme targeting but also the availability of intact GNPTG required for phosphotransferase activity and assembly of subunits. © 2006 Wiley-Liss, Inc.
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Missense mutations in N-acetylglucosamine-1-phosphotransferase alpha/beta subunit gene in a patient with mucolipidosis III and a mild clinical phenotype.
American Journal of Medical Genetics Part A, 2005Co-Authors: Stephan Tiede, Michael Cantz, Nicole Muschol, Gert Reutter, Kurt Ullrich, Thomas BraulkeAbstract: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.
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Missense mutations in N-acetylglucosamine-1-phosphotransferase α/β subunit gene in a patient with mucolipidosis III and a mild clinical phenotype†
American Journal of Medical Genetics Part A, 2005Co-Authors: Stephan Tiede, Michael Cantz, Nicole Muschol, Gert Reutter, Kurt Ullrich, Thomas BraulkeAbstract: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 γ 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 α/β 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. © 2005 Wiley-Liss, Inc.
Nicole Muschol - One of the best experts on this subject based on the ideXlab platform.
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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.
American Journal of Medical Genetics Part A, 2009Co-Authors: Sandra Pohl, Nicole Muschol, Marisa Encarnacão, Monica Castrichini, Sven Müller-loennies, Thomas BraulkeAbstract: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.
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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.
American Journal of Medical Genetics Part A, 2009Co-Authors: Sandra Pohl, Nicole Muschol, Marisa Encarnacão, Monica Castrichini, Sven Müller-loennies, Thomas BraulkeAbstract: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 γ-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 γ-subunit protein. These data contribute to an efficient diagnostic strategy to identify Patients with MLIII gamma and characterize their biochemical defect in fibroblasts. © 2009 Wiley-Liss, Inc.
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Missense mutations in N-acetylglucosamine-1-phosphotransferase alpha/beta subunit gene in a patient with mucolipidosis III and a mild clinical phenotype.
American Journal of Medical Genetics Part A, 2005Co-Authors: Stephan Tiede, Michael Cantz, Nicole Muschol, Gert Reutter, Kurt Ullrich, Thomas BraulkeAbstract: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.
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Missense mutations in N-acetylglucosamine-1-phosphotransferase α/β subunit gene in a patient with mucolipidosis III and a mild clinical phenotype†
American Journal of Medical Genetics Part A, 2005Co-Authors: Stephan Tiede, Michael Cantz, Nicole Muschol, Gert Reutter, Kurt Ullrich, Thomas BraulkeAbstract: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 γ 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 α/β 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. © 2005 Wiley-Liss, Inc.
Sandra Pohl - One of the best experts on this subject based on the ideXlab platform.
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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.
American Journal of Medical Genetics Part A, 2009Co-Authors: Sandra Pohl, Nicole Muschol, Marisa Encarnacão, Monica Castrichini, Sven Müller-loennies, Thomas BraulkeAbstract: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.
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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.
American Journal of Medical Genetics Part A, 2009Co-Authors: Sandra Pohl, Nicole Muschol, Marisa Encarnacão, Monica Castrichini, Sven Müller-loennies, Thomas BraulkeAbstract: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 γ-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 γ-subunit protein. These data contribute to an efficient diagnostic strategy to identify Patients with MLIII gamma and characterize their biochemical defect in fibroblasts. © 2009 Wiley-Liss, Inc.
T Cundy - One of the best experts on this subject based on the ideXlab platform.
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the osteodystrophy of mucolipidosis type iii and the effects of intravenous pamidronate treatment
Journal of Inherited Metabolic Disease, 2002Co-Authors: C Robinson, N Baker, J Noble, A King, G David, David Sillence, P Hofman, T CundyAbstract:Summary: Mucolipidosis type III (ML III; McKusick 252600) is a rare lysosomal storage disease in which skeletal involvement is prominent, in particular the destruction of vertebral bodies and the femoral heads. We describe studies in two siblings with ML III that suggest the presence of a distinct metabolic bone disorder. Biochemical indices of bone turnover were increased, and transiliac bone biopsy demonstrated both trabecular osteopenia and marked subperiosteal bone resorption. Intravenous pamidronate treatment given monthly for a year was well tolerated and produced dramatic clinical effects, with reduction in bone pain and improvements in mobility, despite incomplete suppression of bone resorption as assessed by biochemical, radiographic and histological criteria. Bisphosphonate therapy may have an important role in the management of bone pain in ML III, as it does in the related lysosomal disorder of Gaucher disease. Mucolipidosis type III (McKusick 252600, also known as Pseudo-Hurler Polydystrophy) is a recessively inherited lysosomal storage disease. These disorders arise from defects in lysosomal enzymes responsible for the breakdown of complex molecules, such as glycosaminoglycans. Tissue damage develops as a result of the accumulation of incompletely processed macromolecules. The differing clinical phenotypes of the lysosomal storage disorders reflect the enzyme that is defective, the products that accumulate, and the particular tissues in which they accumulate. In the case of mucolipidosis type III, which was first described by Maroteaux
Marisa Encarnacão - One of the best experts on this subject based on the ideXlab platform.
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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.
American Journal of Medical Genetics Part A, 2009Co-Authors: Sandra Pohl, Nicole Muschol, Marisa Encarnacão, Monica Castrichini, Sven Müller-loennies, Thomas BraulkeAbstract: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.
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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.
American Journal of Medical Genetics Part A, 2009Co-Authors: Sandra Pohl, Nicole Muschol, Marisa Encarnacão, Monica Castrichini, Sven Müller-loennies, Thomas BraulkeAbstract: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 γ-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 γ-subunit protein. These data contribute to an efficient diagnostic strategy to identify Patients with MLIII gamma and characterize their biochemical defect in fibroblasts. © 2009 Wiley-Liss, Inc.
