Related Experiment Video
Updated: Mar 1, 2026
Author Spotlight: Generating Neuronal Phenotypic Profiles - A Protocol to Culture and Image Human Midbrain Dopaminergic Neurons
Published on: July 7, 2023
Genotype-phenotype relationship in mucopolysaccharidosis II: predictive power of IDS variants for the neuronopathic
Audrey A M Vollebregt1,2, Marianne Hoogeveen-Westerveld1,3, Marian A Kroos1,3
1Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
Aim:
Mucopolysaccharidosis type II (MPS II) is caused by variants in the iduronate-2-sulphatase gene (IDS). Patients can be either neuronopathic with intellectual disability, or non-neuronopathic. Few studies have reported on the IDS genotype-phenotype relationship and on the molecular effects involved. We addressed this in a cohort study of Dutch patients with MPS II.
Method:
Intellectual performance was assessed for school performance, behaviour, and intelligence. Urinary glycosaminoglycans were quantified by mass spectrometry. IDS variants were analysed in expression studies for enzymatic activity and processing by immunoblotting.
Results:
Six patients had a non-neuronopathic phenotype and 11 a neuronopathic phenotype, three of whom had epilepsy. Total deletion of IDS invariably resulted in the neuronopathic phenotype. Phenotypes of seven known IDS variants were consistent with the literature. Expression studies of nine variants were novel and showed impaired IDS enzymatic activity, aberrant intracellular processing, and elevated urinary excretion of heparan sulphate and dermatan sulphate irrespective of the MPS II phenotype.
Interpretation:
We speculate that very low or cell-type-specific IDS residual activity is sufficient to prevent the neuronal phenotype of MPS II. Whereas the molecular effects of IDS variants do not distinguish between MPS II phenotypes, the IDS genotype is a strong predictor.
Insights
Mucopolysaccharidosis type II (MPS II) is linked to the IDS gene. While molecular effects of IDS variants don't predict phenotype, the specific IDS genotype strongly predicts whether patients develop neuronopathic MPS II.
Area of Science:
- Genetics
- Biochemistry
- Rare Diseases
Background:
- Mucopolysaccharidosis type II (MPS II) is a genetic disorder caused by variants in the iduronate-2-sulphatase gene (IDS).
- Patients present with either neuronopathic (intellectual disability) or non-neuronopathic phenotypes.
- Limited research exists on the genotype-phenotype correlation and molecular mechanisms in MPS II.
Purpose of the Study:
- To investigate the genotype-phenotype relationship in Dutch MPS II patients.
- To explore the molecular effects of IDS variants.
- To correlate IDS variants with clinical presentation and biochemical findings.
Main Methods:
- Cohort study of Dutch patients with MPS II.
- Assessment of intellectual performance, behavior, and intelligence.
- Quantification of urinary glycosaminoglycans via mass spectrometry.
- Analysis of IDS variants through expression studies, enzymatic activity assays, and immunoblotting.
Main Results:
- Identified 6 non-neuronopathic and 11 neuronopathic phenotypes (3 with epilepsy).
- Total IDS deletion invariably led to the neuronopathic phenotype.
- Novel expression studies revealed impaired IDS enzymatic activity and processing for 9 variants, with elevated heparan and dermatan sulfate excretion, irrespective of phenotype.
Conclusions:
- Very low or cell-type-specific residual IDS activity may prevent the neuronopathic phenotype in MPS II.
- Molecular effects of IDS variants do not differentiate between MPS II phenotypes.
- The IDS genotype is a significant predictor of the MPS II phenotype.
Related Concept Videos
01:35Pedigree Analysis
01:33Pleiotropy
01:11Genetic Lingo
01:43Incomplete Dominance
01:21EPS and iPS Cells in Disease Research
01:37Neural Regulation