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Heidari E, Harrison AN, Jafarinia E, et al. Novel variants in critical domains of ATP8A2 and expansion of clinical spectrum. Hum Mutat. 2021;42(5):491-497doi: 10.1002/humu.24180.
Heidari, E., Harrison, A. N., Jafarinia, E., Tavasoli, A. R., Almadani, N., Molday, R. S., & Garshasbi, M. (2021). Novel variants in critical domains of ATP8A2 and expansion of clinical spectrum. Human mutation, 42(5), 491-497. https://doi.org/10.1002/humu.24180
Heidari, Erfan, et al. "Novel variants in critical domains of ATP8A2 and expansion of clinical spectrum." Human mutation vol. 42,5 (2021): 491-497. doi: https://doi.org/10.1002/humu.24180
Heidari E, Harrison AN, Jafarinia E, Tavasoli AR, Almadani N, Molday RS, Garshasbi M. Novel variants in critical domains of ATP8A2 and expansion of clinical spectrum. Hum Mutat. 2021 May;42(5):491-497. doi: 10.1002/humu.24180. Epub 2021 Mar 14. PMID: 33565221.
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Hum Mutat. 2021 May;42(5):491-497. doi: 10.1002/humu.24180. Epub 2021 Mar 14.

Novel variants in critical domains of ATP8A2 and expansion of clinical spectrum.

Human mutation

Erfan Heidari, Alexander N Harrison, Ehsan Jafarinia, Ali Reza Tavasoli, Navid Almadani, Robert S Molday, Masoud Garshasbi

Affiliations

  1. Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
  2. Department of Biochemistry & Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
  3. Division of Pediatric Neurology, Myelin Disorders Clinic, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
  4. Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.

PMID: 33565221 DOI: 10.1002/humu.24180

Abstract

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 with the Mg

© 2021 Wiley Periodicals LLC.

Keywords: ATP8A2; P4-ATPase; loss of function; phosphatidylserine flippase; tooth abnormalities

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