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

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; Kovacs-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; P?oski, Rafa?; Hoffmann, Georg F; Pronicki, Maciej; Bonnen, Penelope E; Morlot, Susanne; Haack, Tobias B     «

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; Kovacs-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...     »

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.      «

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 d...     »