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Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy. American journal of human genetics Danhauser, K. n., Alhaddad, B. n., Makowski, C. n., Piekutowska-Abramczuk, D. n., Syrbe, S. n., Gomez-Ospina, N. n., Manning, M. A., Kostera-Pruszczyk, A. n., Krahn-Peper, C. n., Berutti, R. n., Kovács-Nagy, R. n., Gusic, M. n., Graf, E. n., Laugwitz, L. n., Röblitz, M. n., Wroblewski, A. n., Hartmann, H. n., Das, A. M., Bültmann, E. n., Fang, F. n., Xu, M. n., Schatz, U. A., Karall, D. n., Zellner, H. n., Haberlandt, E. n., Feichtinger, R. G., Mayr, J. A., Meitinger, T. n., Prokisch, H. n., Strom, T. M., Ploski, R. n., Hoffmann, G. F., Pronicki, M. n., Bonnen, P. E., Morlot, S. n., Haack, T. B. 2018; 103 (5): 817–25

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.

View details for PubMedID 30401461