Heidari Erfan, Harrison Alexander N, Jafarinia Ehsan, Tavasoli Ali Reza, Almadani Navid, Molday Robert S, Garshasbi Masoud
Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Department of Biochemistry & Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
Hum Mutat. 2021 May;42(5):491-497. doi: 10.1002/humu.24180. Epub 2021 Mar 14.
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 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.
ATP8A2是一种P4-ATP酶，它能使磷脂酰丝氨酸跨膜翻转，以产生并维持跨膜磷脂不对称性。功能丧失型变异会导致严重的神经退行性疾病和发育障碍。我们在不相关的伊朗家庭中鉴定出三种ATP8A2变异，这些变异会导致智力残疾、肌张力障碍、头围低于平均水平、轻度视神经萎缩和发育迟缓。此外，所有受影响个体均表现出与牙齿发育缺陷相关的牙齿异常。两种变异（p.Asp825His和p.Met438Val）位于ATP8A2的关键功能域。这些变异表达水平极低且缺乏ATP酶活性。抑制剂研究表明，这些变异会错误折叠并被细胞蛋白酶体降解。我们得出结论，在ATP结合位点与镁离子配位的Asp825以及Met438对于ATP8A2正确折叠成功能性翻转酶至关重要。我们还提供了牙齿异常与ATP8A2缺陷之间关联的证据，从而扩大了相关疾病的临床谱。
