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Molecular and cellular basis of ornithine δ-aminotransferase deficiency caused by the V332M mutation associated with gyrate atrophy of the choroid and retina
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Italy.
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2018 (English)In: Biochimica et Biophysica Acta - Molecular Basis of Disease, ISSN 0925-4439, E-ISSN 1879-260X, Vol. 1864, no 11, p. 3629-3638Article in journal (Refereed) Published
Abstract [en]

Gyrate atrophy (GA) is a rare recessive disorder characterized by progressive blindness, chorioretinal degeneration and systemic hyperornithinemia. GA is caused by point mutations in the gene encoding ornithine δ-aminotransferase (OAT), a tetrameric pyridoxal 5′-phosphate-dependent enzyme catalysing the transamination of l-ornithine and α-ketoglutarate to glutamic–γ-semialdehyde and l-glutamate in mitochondria. More than 50 OAT variants have been identified, but their molecular and cellular properties are mostly unknown. A subset of patients is responsive to pyridoxine administration, although the mechanisms underlying responsiveness have not been clarified. Herein, we studied the effects of the V332M mutation identified in pyridoxine-responsive patients. The Val332-to-Met substitution does not significantly affect the spectroscopic and kinetic properties of OAT, but during catalysis it makes the protein prone to convert into the apo-form, which undergoes unfolding and aggregation under physiological conditions. By using the CRISPR/Cas9 technology we generated a new cellular model of GA based on HEK293 cells knock-out for the OAT gene (HEK-OAT_KO). When overexpressed in HEK-OAT_KO cells, the V332M variant is present in an inactive apodimeric form, but partly shifts to the catalytically-competent holotetrameric form in the presence of exogenous PLP, thus explaining the responsiveness of these patients to pyridoxine administration. Overall, our data represent the first integrated molecular and cellular analysis of the effects of a pathogenic mutation in OAT. In addition, we validated a novel cellular model for the disease that could prove instrumental to define the molecular defect of other GA-causing variants, as well as their responsiveness to pyridoxine and other putative drugs.

Place, publisher, year, edition, pages
Elsevier, 2018. Vol. 1864, no 11, p. 3629-3638
Keywords [en]
Rare disease, Pyridoxal phosphate, Ornithine aminotransferase, Pathogenic mutation, Pyridoxine
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-153117DOI: 10.1016/j.bbadis.2018.08.032ISI: 000447477400007PubMedID: 30251682Scopus ID: 2-s2.0-85052646089OAI: oai:DiVA.org:umu-153117DiVA, id: diva2:1262623
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2019-01-09Bibliographically approved

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Doimo, Mara

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