Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy PMID: 30401461

Target-related Cytokines

2026-09-23

Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy

Am J Hum Genet. 2018 Nov 1;103(5):817-825. doi: 10.1016/j.ajhg.2018.10.005.

Katharina Danhauser ¹ , Bader Alhaddad ² , Christine Makowski ³ , Dorota Piekutowska-Abramczuk ⁴ , Steffen Syrbe ⁵ , Natalia Gomez-Ospina ⁶ , Melanie A Manning ⁶ , Anna Kostera-Pruszczyk ⁷ , Claudia Krahn-Peper ⁸ , Riccardo Berutti ⁹ , Reka Kovács-Nagy ¹⁰ , Mirjana Gusic ² , Elisabeth Graf ⁹ , Lucia Laugwitz ¹¹ , Michaela Röblitz ¹² , Andreas Wroblewski ¹² , Hans Hartmann ¹³ , Anibh M Das ¹³ , Eva Bültmann ¹⁴ , Fang Fang ¹⁵ , Manting Xu ¹⁵ , Ulrich A Schatz ¹⁶ , Daniela Karall ¹⁷ , Herta Zellner ¹⁷ , Edda Haberlandt ¹⁸ , René G Feichtinger ¹⁹ , Johannes A Mayr ¹⁹ , Thomas Meitinger ²⁰ , Holger Prokisch ²¹ , Tim M Strom ² , Rafał Płoski ²² , Georg F Hoffmann ⁵ , Maciej Pronicki ²³ , Penelope E Bonnen ²⁴ , Susanne Morlot ²⁵ , Tobias B Haack ²⁶

Affiliations

1. Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University of Munich, 80337 Munich, Germany.
2. Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
3. Department of Pediatrics, Technische Universität München, 80804 Munich, Germany.
4. Department of Medical Genetics, Children's Memorial Health Institute, 04-730 Warsaw, Poland.
5. Division of Neuropediatrics and Metabolic Medicine, University Children's Hospital, 69120 Heidelberg, Germany.
6. Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
7. Department of Neurology, Medical University of Warsaw, 02-097 Warsaw, Poland.
8. Sozialpädiatrisches Zentrum, Heilpädagogisch Therapeutisches Zentrum gGmbH, 56564 Neuwied, Germany.
9. Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
10. Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
11. Division of Pediatric Neurology and Developmental Medicine, University Children's Hospital, 72072 Tübingen, Germany; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany.
12. St. Joseph Krankenhaus, Zentrum Kinder- und Jugendmedizin, Wüsthoffstr. 15, 12101 Berlin, Germany.
13. Clinic for Pediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, 30625 Hannover, Germany.
14. Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, 30625 Hannover, Germany.
15. Department of Pediatric Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 100045 Beijing, China.
16. Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Division of Human Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
17. Clinic for Pediatrics, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, 6020 Innsbruck, Austria.
18. Clinic for Pediatrics, Krankenhaus Stadt Dornbirn, 6850 Dornbirn, Austria.
19. Department of Pediatrics, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.
20. Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, German.
21. Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Department of Pediatric Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 100045 Beijing, China.
22. Department of Medical Genetics, Medical University of Warsaw, 02-106 Warsaw, Poland.
23. Department of Pathology, Children's Memorial Health Institute, 04-730 Warsaw, Poland.
24. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
25. Institute of Human Genetics, Hannover Medical School, 30625 Hannover, Germany.
26. Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tübingen, Germany. Electronic address: [email protected].

Abstract

ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADP-ribose from NAD⁺ to the target protein, and ADP-ribosylhydrolases, such as ADPRHL2, reverse the reaction. We used exome Sequencing to identify five different bi-allelic pathogenic ADPRHL2 variants in 12 individuals from 8 families affected by a neurodegenerative disorder manifesting in childhood or adolescence with key clinical features including developmental delay or regression, seizures, ataxia, and axonal (sensori-)motor neuropathy. ADPRHL2 was virtually absent in available affected individuals' fibroblasts, and cell viability was reduced upon hydrogen peroxide exposure, although it was rescued by expression of wild-type ADPRHL2 mRNA as well as treatment with a PARP1 Inhibitor. Our findings suggest impaired protein ribosylation as another pathway that, if disturbed, causes neurodegenerative diseases.

Keywords

ADPRHL2; ARH3; PARP; ataxia; cerebellar atrophy; neurodegeneration; neuropathy; posttranslational modification; ribosylation; seizure.