CYP2U1 activity is altered by missense mutations in hereditary spastic paraplegia 56

Christelle Durand 1 Laura Dhers 2 Christelle Tesson 3 Alessandra Tessa 4 Laetitia Fouillen 5 Stéphanie Jacqueré 6 Laure Raymond 7 Isabelle Coupry 8 Giovanni Benard 9 Frédéric Darios 3 Khalid El-Hachimi 3, 10 Guja Astrea 11 François Rivier 12, 13 Guillaume Banneau 14 Claire Pujol 3 Didier Lacombe 15 Alexandra Dürr 3 Patrick Babin 6 Filippo Santorelli 16 Nicolas Pietrancosta 2 Jean-Luc Boucher 2 Daniel Mansuy 2 Giovanni Stevanin 10 Cyril Goizet 17
Abstract : 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.
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Christelle Durand, Laura Dhers, Christelle Tesson, Alessandra Tessa, Laetitia Fouillen, et al.. CYP2U1 activity is altered by missense mutations in hereditary spastic paraplegia 56. Human Mutation, Wiley, 2018, 39 (1), pp.140 - 151. ⟨10.1002/humu.23359⟩. ⟨hal-01796579⟩

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