CYP2U1 activity is altered by missense mutations in hereditary spastic paraplegia 56
- PMID: 29034544
- DOI: 10.1002/humu.23359
CYP2U1 activity is altered by missense mutations in hereditary spastic paraplegia 56
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.
Keywords: CYP2U1; SPG56; arachidonic acid metabolism; biological validation; diagnosis.
© 2017 Wiley Periodicals, Inc.
Similar articles
-
Pseudoxanthoma elasticum overlaps hereditary spastic paraplegia type 56.J Intern Med. 2021 May;289(5):709-725. doi: 10.1111/joim.13193. Epub 2021 Mar 31. J Intern Med. 2021. PMID: 33107650
-
An atypical case of SPG56/CYP2U1-related spastic paraplegia presenting with delayed myelination.J Hum Genet. 2017 Nov;62(11):997-1000. doi: 10.1038/jhg.2017.77. Epub 2017 Jul 20. J Hum Genet. 2017. PMID: 28725025
-
CYP2U1 mutations in two Iranian patients with activity induced dystonia, motor regression and spastic paraplegia.Eur J Paediatr Neurol. 2016 Sep;20(5):782-7. doi: 10.1016/j.ejpn.2016.05.013. Epub 2016 Jun 2. Eur J Paediatr Neurol. 2016. PMID: 27292318 Free PMC article.
-
Cytochrome P450 2U1, a very peculiar member of the human P450s family.Cell Mol Life Sci. 2017 May;74(10):1859-1869. doi: 10.1007/s00018-016-2443-3. Epub 2017 Jan 12. Cell Mol Life Sci. 2017. PMID: 28083596 Free PMC article. Review.
-
Hereditary spastic paraplegia associated with a rare IFIH1 mutation: a case report and literature review.Hereditas. 2019 Aug 13;156:28. doi: 10.1186/s41065-019-0104-x. eCollection 2019. Hereditas. 2019. PMID: 31427910 Free PMC article. Review.
Cited by
-
Diagnostic journey and genetic analysis of a novel homozygous CYP2U1 mutation causing autosomal recessive spastic paraplegia type 56 (SPG56) in a consanguineous family.BMC Neurol. 2025 May 15;25(1):207. doi: 10.1186/s12883-025-04211-7. BMC Neurol. 2025. PMID: 40375209 Free PMC article.
-
Pleiotropy of Progesterone Receptor Membrane Component 1 in Modulation of Cytochrome P450 Activity.J Xenobiot. 2024 May 1;14(2):575-603. doi: 10.3390/jox14020034. J Xenobiot. 2024. PMID: 38804287 Free PMC article. Review.
-
Spastic Paraplegia-56 due to a Novel CYP2U1 Truncating Mutation in an Indian Boy: A New Report and Literature Review.J Pediatr Neurosci. 2021 Jan-Mar;16(1):71-74. doi: 10.4103/jpn.JPN_86_20. Epub 2021 Jun 25. J Pediatr Neurosci. 2021. PMID: 34316314 Free PMC article.
-
Brain Calcifications: Genetic, Molecular, and Clinical Aspects.Int J Mol Sci. 2023 May 19;24(10):8995. doi: 10.3390/ijms24108995. Int J Mol Sci. 2023. PMID: 37240341 Free PMC article. Review.
-
Implication of folate deficiency in CYP2U1 loss of function.J Exp Med. 2021 Nov 1;218(11):e20210846. doi: 10.1084/jem.20210846. Epub 2021 Sep 21. J Exp Med. 2021. PMID: 34546337 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources