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Bi-allelic ADPRHL2 mutations cause neurodegeneration with developmental delay, ataxia, and axaonal neuropathy.
Am. J. Hum. Genet. 103, 817-825 (2018)
DOI
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Adprhl2 ; Arh3 ; Parp ; Ataxia ; Cerebellar Atrophy ; Neurodegeneration ; Neuropathy ; Posttranslational Modification ; Ribosylation ; Seizure; Poly Adp-ribose; Poly(adp-ribose) Glycohydrolase; Cell-death; Disease; Degradation; Deficiency; Enzymes
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Zeitschrift American Journal of Human Genetics, The
Quellenangaben Band: 103, Heft: 5, Seiten: 817-825 Artikelnummer: , Supplement: ,
Verlag Elsevier ; Cell Press
Verlagsort New York, NY
Begutachtungsstatus peer-reviewed