2. Academic Validation
  3. Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy

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

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: tobias.haack@med.uni-tuebingen.de.
PMID: 30401461 DOI: 10.1016/j.ajhg.2018.10.005
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.

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