Journal
HUMAN MUTATION
Volume 39, Issue 1, Pages 140-151Publisher
WILEY
DOI: 10.1002/humu.23359
Keywords
arachidonic acid metabolism; biological validation; CYP2U1; diagnosis; SPG56
Categories
Funding
- French National Research Agency [2013BLANC/SPATAX-QUEST, 2010BLAN112601/LIGENAX]
- Association Francaise contre les Myopathies [14879/MNM22012, 16065]
- Association Strumpell-Lorrain [2011-0135]
- Conseil Regional d'Aquitaine [2011-0151/LIGENAX]
- Association against Mitochondrial Diseases
- E-rare Programme
- 7th Framework Programme of the European Union
Ask authors/readers for more resources
Hereditary spastic paraplegia (HSP) is an inherited disorder of the central nervous system mainly characterized by gradual spasticity and weakness of the lower limbs. SPG56 is a rare autosomal recessive early onset complicated form of HSP caused by mutations in CYP2U1. The CYP2U1 enzyme was shown to catalyze the hydroxylation of arachidonic acid. Here, we report two further SPG56 families carrying three novel CYP2U1 missense variants and the development of an in vitro biochemical assay to determine the pathogenicity of missense variants of uncertain clinical significance. We compared spectroscopic, enzymatic, and structural (from a 3D model) characteristics of the over expressed wild-type or mutated CYP2U1 in HEK293T cells. Our findings demonstrated that most of the tested missense variants in CYP2U1 were functionally inactive because of a loss of proper heme binding or destabilization of the protein structure. We also showed that functional data do not necessarily correlate with in silico predictions of variants pathogenicity, using different bioinformatic phenotype prediction tools. Our results therefore highlight the importance to use biological tools, such as the enzymatic test set up in this study, to evaluate the effects of newly identified variants in clinical settings.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available