Novel variants in critical domains of ATP8A2 and expansion of clinical spectrum
| Autor: | Alexander N Harrison, Masoud Garshasbi, Ehsan Jafarinia, Ali Reza Tavasoli, Robert S. Molday, Navid Almadani, Erfan Heidari |
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| Rok vydání: | 2021 |
| Předmět: |
Cytoplasm
Biology Iran 03 medical and health sciences chemistry.chemical_compound Atrophy Protein Domains Intellectual disability Genetics medicine Humans Phospholipid Transfer Proteins Genetics (clinical) Loss function Phospholipids 030304 developmental biology Dystonia Adenosine Triphosphatases 0303 health sciences 030305 genetics & heredity Flippase Phosphatidylserine medicine.disease Transmembrane protein Proteasome chemistry |
| Zdroj: | Human mutationREFERENCES. 42(5) |
| ISSN: | 1098-1004 |
| Popis: | ATP8A2 is a P4-ATPase that flips phosphatidylserine across membranes to generate and maintain transmembrane phospholipid asymmetry. Loss-of-function variants cause severe neurodegenerative and developmental disorders. We have identified three ATP8A2 variants in unrelated Iranian families that cause intellectual disability, dystonia, below-average head circumference, mild optic atrophy, and developmental delay. Additionally, all the affected individuals displayed tooth abnormalities associated with defects in teeth development. Two variants (p.Asp825His and p.Met438Val) reside in critical functional domains of ATP8A2. These variants express at very low levels and lack ATPase activity. Inhibitor studies indicate that these variants are misfolded and degraded by the cellular proteasome. We conclude that Asp825 which coordinates to the Mg2+ ion within the ATP binding site and Met438 are essential for the proper folding of ATP8A2 into a functional flippase. We also provide evidence on the association of tooth abnormalities with defects in ATP8A2, thereby expanding the clinical spectrum of the associated disease. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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