Enigmatic in vivo GlcNAc-1-phosphotransferase (GNPTG) transcript correction to wild type in two mucolipidosis III gamma siblings homozygous for nonsense mutations

Velho, Renata Voltolini; Ludwig, Nataniel Floriano; Alegra, Taciane; Sperb‐Ludwig, Fernanda; Guarany, Nicole Ruas; Matte, Úrsula; Schwartz, Ida Vanessa Döederlein

doi:10.1038/jhg.2016.13

Cited by 11 publications

(8 citation statements)

References 43 publications

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“…Due to these clinical manifestations, MLIII can be misinterpreted as a rheumatological disorder like juvenile arthritis or progressive pseudorheumatoid arthropathy of childhood. Craniofacial dysmorphism, growth retardation, organomegaly, and cardiorespiratory problems are often absent or appear to be less pronounced than in MLII (Leroy et al, ; Liu et al, ; Oussoren et al, ; Pohl et al, ; Raas‐Rothschild et al, ; Tüysüz et al, ; Velho, Ludwig, et al, ).…”

Section: Diagnosis Of MLII Mliii Alpha/beta and Mliii Gammamentioning

confidence: 99%

The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: Update onGNPTABandGNPTGmutations

et al. 2019

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Mutations in the GNPTAB and GNPTG genes cause mucolipidosis (ML) type II, type III alpha/beta, and type III gamma, which are autosomal recessively inherited lysosomal storage disorders. GNPTAB and GNPTG encode the α/β‐precursor and the γ‐subunit of N‐acetylglucosamine (GlcNAc)‐1‐phosphotransferase, respectively, the key enzyme for the generation of mannose 6‐phosphate targeting signals on lysosomal enzymes. Defective GlcNAc‐1‐phosphotransferase results in missorting of lysosomal enzymes and accumulation of non‐degradable macromolecules in lysosomes, strongly impairing cellular function. MLII‐affected patients have coarse facial features, cessation of statural growth and neuromotor development, severe skeletal abnormalities, organomegaly, and cardiorespiratory insufficiency leading to death in early childhood. MLIII alpha/beta and MLIII gamma are attenuated forms of the disease. Since the identification of the GNPTAB and GNPTG genes, 564 individuals affected by MLII or MLIII have been described in the literature. In this report, we provide an overview on 258 and 50 mutations in GNPTAB and GNPTG, respectively, including 58 novel GNPTAB and seven novel GNPTG variants. Comprehensive functional studies of GNPTAB missense mutations did not only gain insights into the composition and function of the GlcNAc‐1‐phosphotransferase, but also helped to define genotype‐phenotype correlations to predict the clinical outcome in patients.

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Section: Diagnosis Of MLII Mliii Alpha/beta and Mliii Gammamentioning

confidence: 99%

The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: Update onGNPTABandGNPTGmutations

et al. 2019

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“…Joint stiffness, carpal tunnel syndrome, pain in hips, shoulders, hands, and/or ankles, waddling gait, as well as spinal deformities are common features of ML III, leading to clinical diagnosis in childhood [ 5 , 10 ]. Craniofacial dysmorphism, growth retardation, organomegaly, and cardiorespiratory problems are often absent or appear to be less pronounced than in ML II [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. These young patients are often plagued by recurrent respiratory tract infections, including pneumonia, otitis media, and bronchitis.…”

Section: Introductionmentioning

confidence: 99%

Mucolipidoses Overview: Past, Present, and Future

Khan

Tomatsu

2020

IJMS

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Mucolipidosis II and III (ML II/III) are caused by a deficiency of uridine-diphosphate N-acetylglucosamine: lysosomal-enzyme-N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase, EC2.7.8.17), which tags lysosomal enzymes with a mannose 6-phosphate (M6P) marker for transport to the lysosome. The process is performed by a sequential two-step process: first, GlcNAc-1-phosphotransferase catalyzes the transfer of GlcNAc-1-phosphate to the selected mannose residues on lysosomal enzymes in the cis-Golgi network. The second step removes GlcNAc from lysosomal enzymes by N-acetylglucosamine-1-phosphodiester α-N-acetylglucosaminidase (uncovering enzyme) and exposes the mannose 6-phosphate (M6P) residues in the trans-Golgi network, in which the enzymes are targeted to the lysosomes by M6Preceptors. A deficiency of GlcNAc-1-phosphotransferase causes the hypersecretion of lysosomal enzymes out of cells, resulting in a shortage of multiple lysosomal enzymes within lysosomes. Due to a lack of GlcNAc-1-phosphotransferase, the accumulation of cholesterol, phospholipids, glycosaminoglycans (GAGs), and other undegraded substrates occurs in the lysosomes. Clinically, ML II and ML III exhibit quite similar manifestations to mucopolysaccharidoses (MPSs), including specific skeletal deformities known as dysostosis multiplex and gingival hyperplasia. The life expectancy is less than 10 years in the severe type, and there is no definitive treatment for this disease. In this review, we have described the updated diagnosis and therapy on ML II/III.

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“…We previously showed that noncanonical RNA editing or RNA-DNA sequence differences, RDDs, are coupled to R-loops (43,57). We and others have found transversion-type differences between RNA and its underlying DNA sequences (58)(59)(60). There is no enzymatic reaction that converts a purine to a pyrimidine or vice versa.…”

Section: Discussionmentioning

confidence: 99%

RNA abasic sites in yeast and human cells

Liu

Rodriguez

Ross

et al. 2020

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

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RNA abasic sites and the mechanisms involved in their regulation are mostly unknown; in contrast, DNA abasic sites are well-studied. We found surprisingly that, in yeast and human cells, RNA abasic sites are prevalent. When a base is lost from RNA, the remaining ribose is found as a closed-ring or an open-ring sugar with a reactive C1′ aldehyde group. Using primary amine-based reagents that react with the aldehyde group, we uncovered evidence for abasic sites in nascent RNA, messenger RNA, and ribosomal RNA from yeast and human cells. Mass spectroscopic analysis confirmed the presence of RNA abasic sites. The RNA abasic sites were found to be coupled to R-loops. We show that human methylpurine DNA glycosylase cleaves N-glycosidic bonds on RNA and that human apurinic/apyrimidinic endonuclease 1 incises RNA abasic sites in RNA–DNA hybrids. Our results reveal that, in yeast and human cells, there are RNA abasic sites, and we identify a glycosylase that generates these sites and an AP endonuclease that processes them.

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Enigmatic in vivo GlcNAc-1-phosphotransferase (GNPTG) transcript correction to wild type in two mucolipidosis III gamma siblings homozygous for nonsense mutations

Cited by 11 publications

References 43 publications

The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: Update onGNPTABandGNPTGmutations

The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: Update onGNPTABandGNPTGmutations

Mucolipidoses Overview: Past, Present, and Future

RNA abasic sites in yeast and human cells

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