Alu-Alu Recombination Underlying the First Large Genomic Deletion in GlcNAc-Phosphotransferase Alpha/Beta (GNPTAB) Gene in a MLII Alpha/Beta Patient

Coutinho, Maria Francisca; Santos, Liliana; Lacerda, Lúcia; Quental, Sofia; Wibrand, Flemming; Lund, Allan M.; K, Johansen; Prata, Maria João; Alves, Sandra

doi:10.1007/8904_2011_83

Cited by 5 publications

(3 citation statements)

References 23 publications

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“…The cysteine substitution of Arg986 affected neither the localization of the α/β-subunit precursor in the Golgi apparatus nor its proteolytic cleavage into mature subunits. However, the severe phenotype documented for the patient homozygous for this mutation [Coutinho et al, 2012a] suggests that Arg986Cys strongly impairs the GlcNAc-1-phosphotransferase activity either by inhibition of substrate binding or by directly affecting the catalytic center of the enzyme. Recently, Kornfeld and colleagues identified the DNA methyltransferase-associated protein (DMAP) interaction domain (aa 694-818) localized near the C-terminus of the α-subunit, as one of the three substrate binding sites responsible for the binding of lysosomal proteins [Qian et al, 2013].…”

Section: Discussionmentioning

confidence: 99%

“…To date more than 125 different GNPTAB mutations have been described [Paik et al., ; Tiede et al., ,b; Bargal et al., ; Tiede et al., ; Plante et al., ; Tappino et al., ; Encarnação et al., ; Otomo et al., ; Zarghooni and Dittakavi, ; Cathey et al., ; Ma et al., ; Zhan et al., ; Coutinho et al., ,b; Cury et al., ; Yang et al., ]. Almost all MLII patients have nonsense, frameshift, or splice‐site mutations in GNPTAB , and these mutations are usually associated with a more severe clinical course.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…In particular, mutations in GNPTAB cause both the severe type of ML (ML II alpha/beta) and the attenuated type of ML (ML III alpha/beta, or Pseudo-Hurler polydystrophy) [ 89 ]. Some genomic rearrangements altering GNPTAB structure have been described and include a duplication of exon 2 in both ML II and ML III patients [ 89 ], an Alu – Alu -mediated large homozygous genomic deletion (897 bp) encompassing GNPTAB exon 19 in a ML II a/b patient [ 90 ], and a deletion of GNPTAB exon 9 in a Chinese patient in combination with a point mutation [ 91 ].…”

Section: Svs In Lsdsmentioning

confidence: 99%

Detection of Structural Variants by NGS: Revealing Missing Alleles in Lysosomal Storage Diseases

Cognata¹,

Cavallaro²

2022

Biomedicines

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Lysosomal storage diseases (LSDs) are a heterogeneous group of rare multisystem metabolic disorders occurring mostly in infancy and childhood, characterized by a gradual accumulation of non-degraded substrates inside the cells. Although biochemical enzymatic assays are considered the gold standard for diagnosis of symptomatic patients, genotyping is a requirement for inclusion in enzyme replacement programs and is a prerequisite for carrier tests in relatives and DNA-based prenatal diagnosis. The emerging next-generation sequencing (NGS) technologies are now offering a powerful diagnostic tool for genotyping LSDs patients by providing faster, cheaper, and higher-resolution testing options, and are allowing to unravel, in a single integrated workflow SNVs, small insertions and deletions (indels), as well as major structural variations (SVs) responsible for the pathology. Here, we summarize the current knowledge about the most recurrent and private SVs involving LSDs-related genes, review advantages and drawbacks related to the use of the NGS in the SVs detection, and discuss the challenges to bring this type of analysis in clinical diagnostics.

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N-Acetylglucosamine-1-Phosphate Transferase, Alpha/Beta and Gamma Subunits (GNPTAB, GNPTG)

Coutinho¹

2014

Handbook of Glycosyltransferases and Related Genes

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Alu-Alu Recombination Underlying the First Large Genomic Deletion in GlcNAc-Phosphotransferase Alpha/Beta (GNPTAB) Gene in a MLII Alpha/Beta Patient

Cited by 5 publications

References 23 publications

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

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

Detection of Structural Variants by NGS: Revealing Missing Alleles in Lysosomal Storage Diseases

N-Acetylglucosamine-1-Phosphate Transferase, Alpha/Beta and Gamma Subunits (GNPTAB, GNPTG)

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