PUBLICATION
Lysosomal cholesterol accumulation contributes to the movement phenotypes associated with NUS1 haploinsufficiency
- Authors
- Yu, S.H., Wang, T., Wiggins, K., Louie, R.J., Merino, E.F., Skinner, C., Cassera, M.B., Meagher, K., Goldberg, P., Rismanchi, N., Chen, D., Lyons, M.J., Flanagan-Steet, H., Steet, R.
- ID
- ZDB-PUB-210319-12
- Date
- 2021
- Source
- Genetics in medicine : official journal of the American College of Medical Genetics 23(7): 1305-1314 (Journal)
- Registered Authors
- Flanagan-Steet, Heather, Steet, Richard, Wiggins, Kali
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Line
- Cholesterol
- Haploinsufficiency*/genetics
- Humans
- Lysosomes
- Niemann-Pick Disease, Type C*
- Phenotype
- Receptors, Cell Surface/genetics
- Zebrafish/genetics
- PubMed
- 33731878 Full text @ Genet. Med.
Citation
Yu, S.H., Wang, T., Wiggins, K., Louie, R.J., Merino, E.F., Skinner, C., Cassera, M.B., Meagher, K., Goldberg, P., Rismanchi, N., Chen, D., Lyons, M.J., Flanagan-Steet, H., Steet, R. (2021) Lysosomal cholesterol accumulation contributes to the movement phenotypes associated with NUS1 haploinsufficiency. Genetics in medicine : official journal of the American College of Medical Genetics. 23(7):1305-1314.
Abstract
Purpose Variants in NUS1 are associated with a congenital disorder of glycosylation, developmental and epileptic encephalopathies, and are possible contributors to Parkinson disease pathogenesis. How the diverse functions of the NUS1-encoded Nogo B receptor (NgBR) relate to these different phenotypes is largely unknown. We present three patients with de novo heterozygous variants in NUS1 that cause a complex movement disorder, define pathogenic mechanisms in cells and zebrafish, and identify possible therapy.
Methods Comprehensive functional studies were performed using patient fibroblasts, and a zebrafish model mimicking NUS1 haploinsufficiency.
Results We show that de novo NUS1 variants reduce NgBR and Niemann-Pick type C2 (NPC2) protein amount, impair dolichol biosynthesis, and cause lysosomal cholesterol accumulation. Reducing nus1 expression 50% in zebrafish embryos causes abnormal swim behaviors, cholesterol accumulation in the nervous system, and impaired turnover of lysosomal membrane proteins. Reduction of cholesterol buildup with 2-hydroxypropyl-ß-cyclodextrin significantly alleviates lysosomal proteolysis and motility defects.
Conclusion Our results demonstrate that these NUS1 variants cause multiple lysosomal phenotypes in cells. We show that the movement deficits associated with nus1 reduction in zebrafish arise in part from defective efflux of cholesterol from lysosomes, suggesting that treatments targeting cholesterol accumulation could be therapeutic.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping