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

• Published in: American journal of human genetics Vol. 103; no. 5; pp. 817 - 825
• Main Authors: Danhauser, Katharina, Alhaddad, Bader, Makowski, Christine, Piekutowska-Abramczuk, Dorota, Syrbe, Steffen, Gomez-Ospina, Natalia, Manning, Melanie A., Kostera-Pruszczyk, Anna, Krahn-Peper, Claudia, Berutti, Riccardo, Kovács-Nagy, Reka, Gusic, Mirjana, Graf, Elisabeth, Laugwitz, Lucia, Röblitz, Michaela, Wroblewski, Andreas, Hartmann, Hans, Das, Anibh M., Bültmann, Eva, Fang, Fang, Xu, Manting, Schatz, Ulrich A., Karall, Daniela, Zellner, Herta, Haberlandt, Edda, Feichtinger, René G., Mayr, Johannes A., Meitinger, Thomas, Prokisch, Holger, Strom, Tim M., Płoski, Rafał, Hoffmann, Georg F., Pronicki, Maciej, Bonnen, Penelope E., Morlot, Susanne, Haack, Tobias B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2018; Elsevier
• Subjects: Adenosine Diphosphate Ribose - genetics; Adolescent; ADP-Ribosylation - genetics; ADPRHL2; Alleles; ARH3; ataxia; Cerebellar Ataxia - genetics; cerebellar atrophy; Child; Child, Preschool; Developmental Disabilities - genetics; Exome - genetics; Female; Glycoside Hydrolases - genetics; Humans; Infant; Male; Mutation - genetics; Nervous System Malformations - genetics; neurodegeneration; Neurodegenerative Diseases - genetics; neuropathy; PARP; posttranslational modification; Protein Processing, Post-Translational - genetics; ribosylation; seizure; ARH3; seizure; ataxia; ADPRHL2; posttranslational modification; ribosylation; neurodegeneration; neuropathy; PARP; cerebellar atrophy
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2018.10.005

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.