Novel Variants in Critical Domains of Atp8a2 and Expansion of Clinical Spectrum

Novel Variants in Critical Domains of Atp8a2 and Expansion of Clinical Spectrum Publisher Pubmed

Heidari E¹ ; Harrison AN² ; Jafarinia E¹ ; Tavasoli AR³ ; Almadani N⁴ ; Molday RS² ; Garshasbi M¹

Show 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, BC, 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

Source: Human Mutation Published:2021

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 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. © 2021 Wiley Periodicals LLC

2. Reevaluation of the Impact of the Novel Likely Pathogenic Variant C.1286_1288Delaga in the Atp8a2 Gene: A 7-Year Follow-Up With Clinical, Genetic, and Acmg Insights in an Iranian Family, Molecular Genetics and Genomic Medicine (2025)

Experts (# of related papers)

Abbas Tafakhori (1)

Reza Shervin Badv (1)

Style	Citing Format
MLA	Heidari E, et al.. "Novel Variants in Critical Domains of Atp8a2 and Expansion of Clinical Spectrum." Human Mutation, vol. 42, no. 5, 2021, pp. 491-497.
APA	Heidari E, Harrison AN, Jafarinia E, Tavasoli AR, Almadani N, Molday RS, Garshasbi M (2021). Novel Variants in Critical Domains of Atp8a2 and Expansion of Clinical Spectrum. Human Mutation, 42(5), 491-497.
Chicago	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." Human Mutation 42, no. 5 (2021): 491-497.
Harvard	Heidari E et al. (2021) 'Novel Variants in Critical Domains of Atp8a2 and Expansion of Clinical Spectrum', Human Mutation, 42(5), pp. 491-497.
Vancouver	Heidari E, Harrison AN, Jafarinia E, Tavasoli AR, Almadani N, Molday RS, et al.. Novel Variants in Critical Domains of Atp8a2 and Expansion of Clinical Spectrum. Human Mutation. 2021;42(5):491-497.
BibTex	@article{ author = {Heidari E and Harrison AN and Jafarinia E and Tavasoli AR and Almadani N and Molday RS and Garshasbi M}, title = {Novel Variants in Critical Domains of Atp8a2 and Expansion of Clinical Spectrum}, journal = {Human Mutation}, volume = {42}, number = {5}, pages = {491-497}, year = {2021} }
RIS	TY - JOUR AU - Heidari E AU - Harrison AN AU - Jafarinia E AU - Tavasoli AR AU - Almadani N AU - Molday RS AU - Garshasbi M TI - Novel Variants in Critical Domains of Atp8a2 and Expansion of Clinical Spectrum JO - Human Mutation VL - 42 IS - 5 SP - 491 EP - 497 PY - 2021 ER -

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