Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID: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. 1683 5

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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PMID: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. 2003 96