Publications

Molecular and cellular basis of ornithine δ-aminotransferase deficiency caused by the V332M mutation associated with gyrate atrophy of the choroid and retina  (2018)

Authors:
Montioli, Riccardo; Desbats, Maria Andrea; Grottelli, Silvia; Doimo, Mara; Bellezza, Ilaria; Borri Voltattorni, Carla; Salviati, Leonardo; Cellini, Barbara
Title:
Molecular and cellular basis of ornithine δ-aminotransferase deficiency caused by the V332M mutation associated with gyrate atrophy of the choroid and retina
Year:
2018
Type of item:
Articolo in Rivista
Tipologia ANVUR:
Articolo su rivista
Language:
Inglese
Format:
A Stampa
Referee:
Name of journal:
BBA
ISSN of journal:
0925-4439
N° Volume:
1864
Number or Folder:
11
Page numbers:
3629-3638
Keyword:
Ornithine aminotransferase; Pathogenic mutation; Pyridoxal phosphate; Pyridoxine; Rare disease
Short description of contents:
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.
Web page:
https://doi.org/10.1016/j.bbadis.2018.08.032
Product ID:
104356
Handle IRIS:
11562/985814
Last Modified:
November 15, 2022
Bibliographic citation:
Montioli, Riccardo; Desbats, Maria Andrea; Grottelli, Silvia; Doimo, Mara; Bellezza, Ilaria; Borri Voltattorni, Carla; Salviati, Leonardo; Cellini, Barbara, Molecular and cellular basis of ornithine δ-aminotransferase deficiency caused by the V332M mutation associated with gyrate atrophy of the choroid and retina «BBA» , vol. 1864 , n. 112018pp. 3629-3638

Consulta la scheda completa presente nel repository istituzionale della Ricerca di Ateneo IRIS

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