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

Early Presentation ◽

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.

Mucopolysaccharidosis Type I Phenotypically Corrected with Edited Hematopoietic Stem Cells: Instead of altering the IDUA gene, a protein was inserted in a repurposable place in the genome known as a “safe harbor locus”

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.61223 ◽

2020 ◽

Vol 182 (2) ◽

pp. 275-276

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Type I ◽

Safe Harbor ◽

Hematopoietic Stem ◽

Molecular Analysis of Vietnamese Patients with Mucopolysaccharidosis Type I

Life ◽

10.3390/life11111162 ◽

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 ◽

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

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

Cells ◽

10.3390/cells11010129 ◽

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 ◽

Lysosomal Storage ◽

Molecular Features ◽

Specific Analysis ◽

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.

Cervical pachymeningeal hypertrophy as the initial and cardinal manifestation of mucopolysaccharidosis type I in monozygotic twins with a novel mutation in the alpha-l-iduronidase gene

Journal of the Neurological Sciences ◽

10.1016/j.jns.2010.11.022 ◽

2011 ◽

Vol 302 (1-2) ◽

pp. 121-125 ◽

Cited By ~ 3

Author(s):

Yutaka Furukawa ◽

Ayumi Hamaguchi ◽

Ichiro Nozaki ◽

Takashi Iizuka ◽

Takeshi Sasagawa ◽

...

Keyword(s):

Novel Mutation ◽

Monozygotic Twins ◽

Type I ◽

Mucopolysaccharidosis Type I

Evaluation and identification of IDUA gene mutations in Turkishpatients with mucopolysaccharidosis type I

TURKISH JOURNAL OF MEDICAL SCIENCES ◽

10.3906/sag-1411-160 ◽

2016 ◽

Vol 46 ◽

pp. 404-408 ◽

Cited By ~ 6

Author(s):

Nazente ATÇEKEN ◽

Rıza Köksal ÖZGÜL ◽

Didem YÜCEL YILMAZ ◽

Ayşegül TOKATLI ◽

Turgay COŞKUN ◽

...

Keyword(s):

Gene Mutations ◽

Type I ◽

Gene Therapy of Mucopolysaccharidosis Type I Mice: Repeated Administrations and Safety Assessment of pIDUA/Nanoemulsion Complexes

Current Gene Therapy ◽

10.2174/1566523221666210126151420 ◽

2021 ◽

Vol 21 ◽

Author(s):

Michelle Fraga ◽

Roselena Silvestri Schuh ◽

Édina Poletto ◽

Talita Giacomet de Carvalho ◽

Raqueli Teresinha França ◽

...

Keyword(s):

Safety Assessment ◽

Transfection Efficiency ◽

Signs And Symptoms ◽

Type I ◽

Medium Chain Triglycerides ◽

Repeated Administrations ◽

Idua Gene ◽

Mps I

Background: Mucopolysaccharidosis type I (MPS I) is an inherited disorder caused by α-L-iduronidase (IDUA) deficiency. The available treatments are not effective in improving all signs and symptoms of the disease. Objective: : In the present study, we evaluated the transfection efficiency of repeated intravenous administrations of cationic nanoemulsions associated with the plasmid pIDUA (containing IDUA gene). Methods: Cationic nanoemulsions were composed of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(amino[polyethylene glycol]-2000) (DSPE-PEG), 1,2-dioleoyl-sn-glycero-3-trimethylammonium propane (DOTAP), medium chain triglycerides, glycerol, and water and were prepared by high-pressure homogenization and were repeatedly administered to MPS I mice for IDUA production and gene expression. Results: A significant increase in IDUA expression was observed in all organs analyzed, and IDUA activity tended to increase with repeated administrations when compared to our previous report, when mice received a single administration of the same dose. In addition, GAGs were partially cleared from organs, as assessed through biochemical and histology analyzes. There was no presence of inflammatory infiltrate, necrosis, or signs of increase in apoptosis. Furthermore, immunohistochemistry for CD68 showed reduced presence of macrophage cells in treated than in untreated MPS I mice. Conclusion: These set of results suggest that repeated administrations can improve transfection efficiency of cationic complexes without significant increase in toxicity in the MPS I murine model.