scholarly journals Drosophila D-idua Reduction Mimics Mucopolysaccharidosis Type I Disease-Related Phenotypes

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 129
Author(s):  
Concetta De Filippis ◽  
Barbara Napoli ◽  
Laura Rigon ◽  
Giulia Guarato ◽  
Reinhard Bauer ◽  
...  
Keyword(s):  
Dermatan Sulfate ◽  
Pupal Stage ◽  
Fruit Fly ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Lysosomal Storage ◽  
Molecular Features ◽  
Specific Analysis ◽  
Idua Gene

Deficit of the IDUA (α-L-iduronidase) enzyme causes the lysosomal storage disorder mucopolysaccharidosis type I (MPS I), a rare pediatric neurometabolic disease, due to pathological variants in the IDUA gene and is characterized by the accumulation of the undegraded mucopolysaccharides heparan sulfate and dermatan sulfate into lysosomes, with secondary cellular consequences that are still mostly unclarified. Here, we report a new fruit fly RNAi-mediated knockdown model of a IDUA homolog (D-idua) displaying a phenotype mimicking some typical molecular features of Lysosomal Storage Disorders (LSD). In this study, we showed that D-idua is a vital gene in Drosophila and that ubiquitous reduction of its expression leads to lethality during the pupal stage, when the precise degradation/synthesis of macromolecules, together with a functional autophagic pathway, are indispensable for the correct development to the adult stage. Tissue-specific analysis of the D-idua model showed an increase in the number and size of lysosomes in the brain and muscle. Moreover, the incorrect acidification of lysosomes led to dysfunctional lysosome-autophagosome fusion and the consequent block of autophagy flux. A concomitant metabolic drift of glycolysis and lipogenesis pathways was observed. After starvation, D-idua larvae showed a quite complete rescue of both autophagy/lysosome phenotypes and metabolic alterations. Metabolism and autophagy are strictly interconnected vital processes that contribute to maintain homeostatic control of energy balance, and little is known about this regulation in LSDs. Our results provide new starting points for future investigations on the disease’s pathogenic mechanisms and possible pharmacological manipulations.

scholarly journals Cathepsin B-associated Activation of Amyloidogenic Pathway in Murine Mucopolysaccharidosis Type I Brain Cortex

2020 ◽  
Vol 21 (4) ◽  
pp. 1459 ◽  
Author(s):  
Gustavo Monteiro Viana ◽  
Esteban Alberto Gonzalez ◽  
Marcela Maciel Palacio Alvarez ◽  
Renan Pelluzzi Cavalheiro ◽  
Cinthia Castro do Nascimento ◽  
...  
Keyword(s):  
Cathepsin B ◽  
Dermatan Sulfate ◽  
Fluorescent Microscopy ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Lysosomal Storage ◽  
App Processing ◽  
Mps I

Mucopolysaccharidosis type I (MPS I) is caused by genetic deficiency of α-l-iduronidase and impairment of lysosomal catabolism of heparan sulfate and dermatan sulfate. In the brain, these substrates accumulate in the lysosomes of neurons and glial cells, leading to neuroinflammation and neurodegeneration. Their storage also affects lysosomal homeostasis-inducing activity of several lysosomal proteases including cathepsin B (CATB). In the central nervous system, increased CATB activity has been associated with the deposition of amyloid plaques due to an alternative pro-amyloidogenic processing of the amyloid precursor protein (APP), suggesting a potential role of this enzyme in the neuropathology of MPS I. In this study, we report elevated levels of protein expression and activity of CATB in cortex tissues of 6-month-old MPS I (Idua -/- mice. Besides, increased CATB leakage from lysosomes to the cytoplasm of Idua -/- cortical pyramidal neurons was indicative of damaged lysosomal membranes. The increased CATB activity coincided with an elevated level of the 16-kDa C-terminal APP fragment, which together with unchanged levels of β-secretase 1 was suggestive for the role of this enzyme in the amyloidogenic APP processing. Neuronal accumulation of Thioflavin-S-positive misfolded protein aggregates and drastically increased levels of neuroinflammatory glial fibrillary acidic protein (GFAP)-positive astrocytes and CD11b-positive activated microglia were observed in Idua -/- cortex by confocal fluorescent microscopy. Together, our results point to the existence of a novel CATB-associated alternative amyloidogenic pathway in MPS I brain induced by lysosomal storage and potentially leading to neurodegeneration.

scholarly journals Incorporation of Second-Tier Biomarker Testing Improves the Specificity of Newborn Screening for Mucopolysaccharidosis Type I

2020 ◽  
Vol 6 (1) ◽  
pp. 10 ◽  
Author(s):  
Dawn S. Peck ◽  
Jean M. Lacey ◽  
Amy L. White ◽  
Gisele Pino ◽  
April L. Studinski ◽  
...  
Keyword(s):  
Newborn Screening ◽  
False Positive ◽  
Dermatan Sulfate ◽  
False Positive Rate ◽  
False Negative ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Second Tier ◽  
Mps I

Enzyme-based newborn screening for Mucopolysaccharidosis type I (MPS I) has a high false-positive rate due to the prevalence of pseudodeficiency alleles, often resulting in unnecessary and costly follow up. The glycosaminoglycans (GAGs), dermatan sulfate (DS) and heparan sulfate (HS) are both substrates for α-l-iduronidase (IDUA). These GAGs are elevated in patients with MPS I and have been shown to be promising biomarkers for both primary and second-tier testing. Since February 2016, we have measured DS and HS in 1213 specimens submitted on infants at risk for MPS I based on newborn screening. Molecular correlation was available for 157 of the tested cases. Samples from infants with MPS I confirmed by IDUA molecular analysis all had significantly elevated levels of DS and HS compared to those with confirmed pseudodeficiency and/or heterozygosity. Analysis of our testing population and correlation with molecular results identified few discrepant outcomes and uncovered no evidence of false-negative cases. We have demonstrated that blood spot GAGs analysis accurately discriminates between patients with confirmed MPS I and false-positive cases due to pseudodeficiency or heterozygosity and increases the specificity of newborn screening for MPS I.

scholarly journals Modeling Mucopolysaccharidosis Type II in the Fruit Fly by Using the RNA Interference Approach

Life ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 263
Author(s):  
Laura Rigon ◽  
Nicole Kucharowski ◽  
Franka Eckardt ◽  
Reinhard Bauer
Keyword(s):  
Rna Interference ◽  
Enzymatic Activity ◽  
Dermatan Sulfate ◽  
Fruit Fly ◽  
Neurological Involvement ◽  
Mucopolysaccharidosis Type ◽  
Type Ii ◽  
Lysosomal Storage ◽  
Mucopolysaccharidosis Type Ii ◽  
Mps Ii

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder that occurs due to the deficit of the lysosomal enzyme iduronate 2-sulfatase (IDS) that leads to the storage of the glycosaminoglycan heparan- and dermatan-sulfate in all organs and tissues. It is characterized by important clinical features and the severe form presents with a heavy neurological involvement. However, almost nothing is known about the neuropathogenesis of MPS II. To address this issue, we developed a ubiquitous, neuronal, and glial-specific knockdown model in Drosophila melanogaster by using the RNA interference (RNAi) approach. Knockdown of the Ids/CG12014 gene resulted in a significant reduction of the Ids gene expression and enzymatic activity. However, glycosaminoglycan storage, survival, molecular markers (Atg8a, Lamp1, Rab11), and locomotion behavior were not affected. Even strongly reduced, IDS-activity was enough to prevent a pathological phenotype in a MPS II RNAi fruit fly. Thus, a Drosophila MPS II model requires complete abolishment of the enzymatic activity.

scholarly journals Molecular Analysis of Vietnamese Patients with Mucopolysaccharidosis Type I

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1162
Author(s):  
Ngoc Thi Bich Can ◽  
Dien Minh Tran ◽  
Thao Phuong Bui ◽  
Khanh Ngoc Nguyen ◽  
Hoang Huy Nguyen ◽  
...  
Keyword(s):  
Autosomal Recessive Disorder ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Direct Dna Sequencing ◽  
Pathogenic Variants ◽  
Vietnamese Population ◽  
Idua Gene ◽  
Classical Characteristic ◽  
Mps I

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder caused by deleterious mutations in the α‑L‑iduronidase (IDUA) gene. Until now, MPS I in Vietnamese has been poorly addressed. Five MPS I patients were studied with direct DNA sequencing using Illumina technology confirming pathogenic variants in the IDUA gene. Clinical characteristics, additional laboratory results, and family history were collected. All patients have presented with the classical characteristic of MPS I, and α‑L‑iduronidase activity was low with the accumulation of glycosaminoglycans. Three variants in the IDUA gene (c.1190‑10C>A (Intronic), c.1046A>G (p.Asp349Gly), c.1862G>C (p.Arg621Pro) were identified. The c.1190‑10C>A variant represents six of the ten disease alleles, indicating a founder effect for MPS I in the Vietnamese population. Using biochemical and genetic analyses, the precise incidence of MPS I in this population should accelerate early diagnosis, newborn screening, prognosis, and optimal treatment

scholarly journals Alpha-L-iduronidase deficiency: A novel mutation resulting in severe early presentation of Mucopolyscaridosis type I and litature review of molecular basis

2021 ◽  
Author(s):  
nuha alzaabi ◽  
muneera sirajum ◽  
Mohd Zaki Al-Wawi ◽  
Mohammed Alsuwaiji
Keyword(s):  
Molecular Basis ◽  
Novel Mutation ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Early Presentation ◽  
Idua Gene

The IDUA gene (MIM 252800) provides instructions for producing alpha-L-iduronidase, which is essential for the breakdown of glycosaminoglycans (GAGs). Mutations in the IDUA gene have been found to cause mucopolysaccharidosis type I (MIM 607014). This leads to the accumulation of GAGs within lysosomes causing different organs to be dysfunctional.

scholarly journals Implementation of Second-Tier Tests in Newborn Screening for Lysosomal Disorders in North Eastern Italy

2019 ◽  
Vol 5 (2) ◽  
pp. 24 ◽  
Author(s):  
Alberto B. Burlina ◽  
Giulia Polo ◽  
Laura Rubert ◽  
Daniela Gueraldi ◽  
Chiara Cazzorla ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Lysosomal Storage Diseases ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Lysosomal Disorders ◽  
North Eastern ◽  
Second Tier

The increasing availability of treatments and the importance of early intervention have stimulated interest in newborn screening for lysosomal storage diseases. Since 2015, 112,446 newborns in North Eastern Italy have been screened for four lysosomal disorders—mucopolysaccharidosis type I and Pompe, Fabry and Gaucher diseases—using a multiplexed tandem mass spectrometry (MS/MS) assay system. We recalled 138 neonates (0.12%) for collection of a second dried blood spot. Low activity was confirmed in 62 (0.06%), who underwent confirmatory testing. Twenty-five neonates (0.02%) were true positive: eight with Pompe disease; seven with Gaucher disease; eight with Fabry disease; and two with Mucopolysaccharidosis type I. The combined incidence of the four disorders was 1 in 4497 births. Except for Pompe disease, a second-tier test was implemented. We conclude that newborn screening for multiple lysosomal storage diseases combined with a second-tier test can largely eliminate false-positives and achieve rapid diagnosis.

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