Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome Shereen G.

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Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome Shereen G. Ghosh, Kerstin Becker, He Huang, Tracy Dixon-Salazar, Guoliang Chai, Vincenzo Salpietro, Lihadh Al-Gazali, Quinten Waisfisz, Haicui Wang, Keith K. Vaux, Valentina Stanley, Andreea Manole, Ugur Akpulat, Marjan M. Weiss, Stephanie Efthymiou, Michael G. Hanna, Carlo Minetti, Pasquale Striano, Livia Pisciotta, Elisa De Grandis, Janine Altmüller, Peter Nürnberg, Holger Thiele, Uluc Yis, Tuncay Derya Okur, Ayse Ipek Polat, Nafise Amiri, Mohammad Doosti, Ehsan Ghayoor Karimani, Mehran B. Toosi, Gabriel Haddad, Mert Karakaya, Brunhilde Wirth, Johanna M. van Hagen, Nicole I. Wolf, Reza Maroofian, Henry Houlden, Sebahattin Cirak, Joseph G. Gleeson The American Journal of Human Genetics Volume 103, Issue 3, Pages 431-439 (September 2018) DOI: 10.1016/j.ajhg.2018.07.010 Copyright © 2018 Terms and Conditions

Figure 1 Pedigrees of Families with Mutations in ADPRHL2 and Their Clinical Presentation (A) Pedigrees of families 1–6 show consanguineous unions (double bar) and a total of 16 affected individuals. Slashes represent deceased individuals. Black shading indicates affected individuals. Gray shading indicates individuals who passed away from SUDEP; however, no DNA is available. (B) Panels show midline sagittal MRI for one affected individual from each of the six families. White arrows indicate cerebellar atrophy, evidenced by widely spaced cerebellar folia. The American Journal of Human Genetics 2018 103, 431-439DOI: (10.1016/j.ajhg.2018.07.010) Copyright © 2018 Terms and Conditions

Figure 2 Truncating and Missense ADPRHL2 Mutations in Six Independent Families Are Predicted to Be Inactivating (A) Schematic of ADPRHL2 depicts the coding sequence spanning six exons and the 5′ and 3′ UTRs. Black arrows indicate the positions of the six identified mutations and their coordinates within the cDNA (Gene ID: 54936). (B) Schematic of ARH3 depicts the mitochondrial localization sequence (MLS) and the ADP-ribosyl-glycohydrolase domain. Black arrows indicate the position and coordinates of the impact of the described mutations. (C) Western blot of fibroblasts from an unrelated control individual (C), the unaffected carrier father (U), and affected individuals IV-II-6 and IV-II-7 from family 1 shows the absence of ARH3 in affected fibroblasts. α-tubulin was used as the loading control. Western blot of fibroblasts from an unrelated control individual (C) and affected individual II-1 from family 3 and the unaffected carrier mother (U) and affected individual II-3 from family 2 shows significantly reduced amounts of ARH3. α-tubulin was used as the loading control. The American Journal of Human Genetics 2018 103, 431-439DOI: (10.1016/j.ajhg.2018.07.010) Copyright © 2018 Terms and Conditions

Figure 3 Premature Death and Locomotor Defects in Drosophila Parg Mutants Are Rescued by Human ADPRHL2 (A) Schematic of a poly-ADP-ribosylated protein and the location of cleavage. PARG and ADPRHL2 both remove poly-ADP-ribose (PAR) from proteins and cleave the same site. Drosophila melanogaster has one PAR-removing enzyme, Parg. (B) Parg27.1 mutant flies (black) show a severe climbing defect, which was rescued by ubiquitous forced expression of Parg (red) or mis-expression of human ADPRHL2 in two different transgenic lines (green and blue). (C) Parg27.1 mutant flies (black) displayed decreased survival, which was rescued with ubiquitous forced expression of Parg (red) and two different transgenic lines expressing human ADPRHL2 (green and blue). Data represent the mean ± SEM of eight experiments. The American Journal of Human Genetics 2018 103, 431-439DOI: (10.1016/j.ajhg.2018.07.010) Copyright © 2018 Terms and Conditions