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Substrate compositional variation with tissue/region and Gba1 mutations in mouse models--implications for Gaucher
Ying Sun1, Wujuan Zhang, You-Hai Xu
1Division of Human Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
Plos One
|March 23, 2013
Summary
Gaucher disease substrate accumulation varies by mutation, organ, and age. Specific GBA1 mutations and saposin C deficiency impact glucosylceramide and glucosylsphingosine levels differently across tissues.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Gaucher disease is caused by mutations in the GBA1 gene, leading to impaired acid β-glucosidase (GCase) activity.
- This deficiency results in the accumulation of substrates like glucosylceramide (GC) and glucosylsphingosine, causing diverse visceral and central nervous system (CNS) manifestations.
Purpose of the Study:
- To characterize the mutation, tissue, and age-dependent accumulation of different GC species.
- To investigate the impact of GBA1 mutations alone or combined with saposin C deficiency on substrate levels.
Main Methods:
- Analysis of glucosylceramide (GC) and glucosylsphingosine species in mice models with specific Gba1 mutations (D409V, V394L, D409H, N370S) and saposin C deficiency (C*).
- Comparison of substrate accumulation across different organs (liver, spleen, brain, lung) and at various ages.
Main Results:
- Gba1 heteroallelic D409V mutations led to visceral GC accumulation, particularly lung GC24:0.
- Combined saposin C deficiency with V394L or D409H homozygosity caused significant GC degradation defects in the brain or visceral tissues, respectively.
- Glucosylsphingosine was poorly degraded in the brain by V394L and D409H GCases and in visceral tissues by D409V GCase.
- The neonatal lethal N370S/N370S genotype showed minimal substrate accumulation.
Conclusions:
- Gaucher disease phenotypes are influenced by age, organ, and mutation-specific quantitative differences in GC and glucosylsphingosine accumulation.
- These findings highlight the complex interplay between GBA1 mutations, saposin C, and substrate metabolism in Gaucher disease pathogenesis.
