A defect in GPI synthesis as a suggested mechanism for the role of ARV1 in intellectual disability and seizures
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ORIGINAL ARTICLE
A defect in GPI synthesis as a suggested mechanism for the role of ARV1 in intellectual disability and seizures Reeval Segel 1 & Adi Aran 2 & Suleyman Gulsuner 3 & Hiroki Nakamura 4 & Tzvia Rosen 1 & Tom Walsh 3 & Hiroto Denda 4 & Sharon Zeligson 1 & Katsuki Eto 4 & Rachel Beeri 1 & Haruka Okai 5 & Mary-Claire King 3 & Ephrat Levy-Lahad 1 & Kouichi Funato 4 & Paul Renbaum 1 Received: 5 March 2020 / Accepted: 5 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Deficiency of the endoplasmic reticulum transmembrane protein ARV1 leads to epileptic encephalopathy in humans and in mice. ARV1 is highly conserved, but its function in human cells is unknown. Studies of yeast arv1 null mutants indicate that it is involved in a number of biochemical processes including the synthesis of sphingolipids and glycosylphosphatidylinositol (GPI), a glycolipid anchor that is attached to the C-termini of many membrane bound proteins. GPI anchors are post-translational modifications, enabling proteins to travel from the endoplasmic reticulum (ER) through the Golgi and to attach to plasma membranes. We identified a homozygous pathogenic mutation in ARV1, p.Gly189Arg, in two brothers with infantile encephalopathy, and characterized the biochemical defect caused by this mutation. In addition to reduced expression of ARV1 transcript and protein in patients’ fibroblasts, complementation tests in yeast showed that the ARV1 p.Gly189Arg mutation leads to deficient maturation of Gas1, a GPI-anchored protein, but does not affect sphingolipid synthesis. Our results suggest, that similar to mutations in other proteins in the GPI-anchoring pathway, including PIGM, PIGA, and PIGQ, ARV1 p.Gly189Arg causes a GPI anchoring defect and leads to early onset epileptic encephalopathy. Keywords Epilepsy/seizure . Genetics . Developmental disorders . Mental retardation . GPI anchor protein . ARV1 Reeval Segel, Adi Aran, Kouichi Funato and Paul Renbaum contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10048-020-00615-4) contains supplementary material, which is available to authorized users. * Reeval Segel [email protected] * Kouichi Funato [email protected] 1
Medical Genetics Institute, Shaare Zedek Medical Center and Hebrew University-Hadassah School of Medicine, P.O.B. 3235, 91031 Jerusalem, Israel
2
Department of Pediatrics, Neuropediatrics Unit, Shaare Zedek Medical Center and Hebrew University-Hadassah School of Medicine, Jerusalem, Israel
3
Departments of Medicine and Genome Sciences, University of Washington, Seattle, WA, USA
4
Graduate School of Biosphere Science, Hiroshima University, 1-4-4, Kagamiyama, Higashi-hiroshima, Hiroshima 739-8528, Japan
5
School of Applied Biological Science, Hiroshima University, 1-4-4, Kagamiyama, Higashi-hiroshima, Hiroshima 739-8528, Japan
Introduction Deficiency of the endoplasmic reticulum transmembrane protein ARV1 leads to epileptic encephalopathy in humans and in mice [1
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