Cellular Lyso-Gb3 Is a Biomarker for Mucolipidosis II.

Area of Science:

• Biochemistry
• Genetics
• Cell Biology

Background:

• Lysosomal storage diseases (LSDs) encompass over 70 conditions arising from defective lysosomal function.
• While some LSDs have established biomarkers and therapies, many present diagnostic and therapeutic challenges.

Purpose of the Study:

• To investigate Globotriaosylsphingosine (Lyso-Gb3) as a potential biomarker for mucolipidosis II/III (ML II/III).
• To assess the diagnostic utility of Lyso-Gb3 in ML II/III patient-derived cells.

Main Methods:

• Analyzed Lyso-Gb3 levels in knock-out cell models for GLA (Fabry disease), GNPTAB (ML II/III), and PSAP (combined saposin deficiency).
• Compared Lyso-Gb3 levels in ML II/III patient skin fibroblasts with normal cells.
• Evaluated the effect of total lysosomal enzyme supplementation on Lyso-Gb3 levels in ML II/III cells.

Main Results:

• Confirmed elevated Lyso-Gb3 in knock-out models for Fabry, ML II/III, and combined saposin deficiency.
• Demonstrated significantly higher Lyso-Gb3 levels in ML II/III patient fibroblasts compared to controls.
• Observed a decrease in Lyso-Gb3 levels following total lysosomal enzyme supplementation in ML II/III cells.

Conclusions:

• Lyso-Gb3 is elevated in ML II/III patient cells.
• Lyso-Gb3 levels decrease upon therapeutic intervention with lysosomal enzymes.
• Lyso-Gb3 represents a promising novel biomarker for ML II/III, addressing a current diagnostic gap.