Transport of the GlcNAc-1-phosphotransferase α/β-Subunit Precursor Protein to the Golgi Apparatus Requires a Combinatorial Sorting Motif

Franke, Mine; Braulke, Thomas; Storch, Stephan

doi:10.1074/jbc.m112.407676

Cited by 25 publications

(30 citation statements)

References 30 publications

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“…The two cytosolic domains of GNPTAB at the N-and C-termini contain motifs that mediate the export or trafficking of the enzyme through the endoplasmic reticulum and Golgi. The importance of the N-terminal domain has been highlighted by recent work from Franke et al 15 showing that the lysine residue at position 4-the same residue mutated in the patients described in this report-affects a neighboring dileucine sequence responsible for the export of the GlcNAc-1-phosphotransferase ab precursor from the endoplasmic reticulum. 15 The possibility that other mutations may be found to result in an identical phenotype cannot be excluded.…”

Section: Discussionmentioning

confidence: 69%

“…The importance of the N-terminal domain has been highlighted by recent work from Franke et al 15 showing that the lysine residue at position 4-the same residue mutated in the patients described in this report-affects a neighboring dileucine sequence responsible for the export of the GlcNAc-1-phosphotransferase ab precursor from the endoplasmic reticulum. 15 The possibility that other mutations may be found to result in an identical phenotype cannot be excluded. It remains to be seen whether other mutations within the N-terminal domain, or perhaps the C-terminal cytosolic domain, are associated with the unique clinical and biochemical features described in the patients reported here.…”

Section: Discussionmentioning

confidence: 69%

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A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain

et al. 2013

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Mucolipidosis (ML) II and ML IIIa/b are allelic autosomal recessive metabolic disorders due to mutations in GNPTAB. The gene encodes the enzyme UDP-GlcNAc-1-phosphotransferase (GNPT), which is critical to proper trafficking of lysosomal acid hydrolases. The ML phenotypic spectrum is dichotomous. Criteria set for defining ML II and ML IIIa/b are inclusive for all but the few patients with phenotypes that span the archetypes. Clinical and biochemical findings of the 'intermediate' ML in eight patients with the c.10A4C missense mutation in GNPTAB are presented to define this intermediate ML and provide a broader insight into ML pathogenesis. Extensive clinical information, including radiographic examinations at various ages, was obtained from a detailed study of all patients. GNPTAB was sequenced in probands and parents. GNPT activity was measured and cathepsin D sorting assays were performed in fibroblasts. Intermediate ML patients who share the c.10A4C/p.K4Q mutation in GNPTAB demonstrate a distinct, consistent phenotype similar to ML II in physical and radiographic features and to ML IIIa/b in psychomotor development and life expectancy. GNPT activity is reduced to 7-12% but the majority of newly synthesized cathepsin D remains intracellular. The GNPTAB c.10A4C/p.K4Q missense allele results in an intermediate ML II/III with distinct clinical and biochemical characteristics. This delineation strengthens the utility of the discontinuous genotypephenotype correlation in ML II and ML IIIa/b and prompts additional studies on the tissue-specific pathogenesis in GNPT-deficient ML.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 69%

A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain

et al. 2013

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“…It will be of interest to find out whether GOLPH3 interacts with other glycosyltransferases in the Golgi. Recently, Franke and colleagues reported that the K4Q mutation impaired a 5 LL 6 -dependent ER export signal in the N-terminal tail of αβ phosphotransferase (20). This was based on the finding that the level of mature β subunit was decreased relative to the αβ precursor, as detected by Western blotting and the accumulation of the mutant in the ER by immunofluorescence microscopy.…”

Section: Discussionmentioning

confidence: 99%

Mislocalization of phosphotransferase as a cause of mucolipidosis III αβ

Meel

Qian

Kornfeld

2014

Proc. Natl. Acad. Sci. U.S.A.

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The lysosomal storage disorder mucolipidosis III αβ is caused by mutations in the αβ subunits of UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (phosphotransferase). This Golgi-localized enzyme mediates the first step in the synthesis of the mannose 6-phosphate recognition marker on lysosomal acid hydrolases, and loss of function results in impaired lysosomal targeting of these acid hydrolases and decreased lysosomal degradation. Here we show that two patient missense mutations, Lys4Gln and Ser15Tyr, in the N-terminal cytoplasmic tail of the α subunit of phosphotransferase impair retention of the catalytically active enzyme in the Golgi complex. This results in mistargeting of the mutant phosphotransferases to lysosomes, where they are degraded, or to the cell surface and release into the medium. The finding that mislocalization of active phosphotransferase is the basis for mucolipidosis III αβ in a subset of patients shows the importance of single residues in the cytoplasmic tail of a Golgi-resident protein for localization to this compartment.

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“…We recently reported an expression analysis of a missense mutation p.Lys4Gln found homozygously in a mildly affected MLIII alpha/beta patient [Franke et al., ]. This mutation reduces the GlcNAc‐1‐phosphotransferase activity to 12% of controls [Kudo et al., ].…”

Section: Discussionmentioning

confidence: 99%

Mucolipidosis II-Related Mutations Inhibit the Exit from the Endoplasmic Reticulum and Proteolytic Cleavage of GlcNAc-1-Phosphotransferase Precursor Protein (GNPTAB)

et al. 2014

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Mucolipidosis (ML) II and MLIII alpha/beta are two pediatric lysosomal storage disorders caused by mutations in the GNPTAB gene, which encodes an α/β-subunit precursor protein of GlcNAc-1-phosphotransferase. Considerable variations in the onset and severity of the clinical phenotype in these diseases are observed. We report here on expression studies of two missense mutations c.242G>T (p.Trp81Leu) and c.2956C>T (p.Arg986Cys) and two frameshift mutations c.3503_3504delTC (p.Leu1168GlnfsX5) and c.3145insC (p.Gly1049ArgfsX16) present in severely affected MLII patients, as well as two missense mutations c.1196C>T (p.Ser399Phe) and c.3707A>T (p.Lys1236Met) reported in more mild affected individuals. We generated a novel α-subunit-specific monoclonal antibody, allowing the analysis of the expression, subcellular localization, and proteolytic activation of wild-type and mutant α/β-subunit precursor proteins by Western blotting and immunofluorescence microscopy. In general, we found that both missense and frameshift mutations that are associated with a severe clinical phenotype cause retention of the encoded protein in the endoplasmic reticulum and failure to cleave the α/β-subunit precursor protein are associated with a severe clinical phenotype with the exception of p.Ser399Phe found in MLIII alpha/beta. Our data provide new insights into structural requirements for localization and activity of GlcNAc-1-phosphotransferase that may help to explain the clinical phenotype of MLII patients.

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Transport of the GlcNAc-1-phosphotransferase α/β-Subunit Precursor Protein to the Golgi Apparatus Requires a Combinatorial Sorting Motif

Cited by 25 publications

References 30 publications

A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain

A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain

Mislocalization of phosphotransferase as a cause of mucolipidosis III αβ

Mucolipidosis II-Related Mutations Inhibit the Exit from the Endoplasmic Reticulum and Proteolytic Cleavage of GlcNAc-1-Phosphotransferase Precursor Protein (GNPTAB)

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