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

作者：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; Roeblitz, Michaela; Wroblewski, Andreas; Hartmann, Hans; Das, Anibh M.; Bueltmann, Eva; Fang, Fang; Xu, Manting; Schatz, Ulrich A.; Karall, Daniela; Zellner, Herta; Haberlandt, Edda; Feichtinger, Rene G.

来源：American Journal of Human Genetics, 2018, 103(5): 817-825.

DOI：10.1016/j.ajhg.2018.10.005

• POLY ADP-RIBOSE
• CELL-DEATH
• POLY(ADP-RIBOSE)
• DEGRADATION
• ENZYMES

ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADPribose 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.

• 出版日期2018-11-1
• 单位河北医科大学; 首都医科大学