Biallelic mutations in ADPRHL2, encoding ADP-ribosylhydrolase 3, lead to a degenerative pediatric stress-induced epileptic ataxia syndrome

Item Type:	Article
Title:	Biallelic mutations in ADPRHL2, encoding ADP-ribosylhydrolase 3, lead to a degenerative pediatric stress-induced epileptic ataxia syndrome
Creators Name:	Ghosh, S.G. and Becker, K. and Huang, H. and Dixon-Salazar, T. and Chai, G. and Salpietro, V. and Al-Gazali, L. and Waisfisz, Q. and Wang, H. and Vaux, K.K. and Stanley, V. and Manole, A. and Akpulat, U. and Weiss, M.M. and Efthymiou, S. and Hanna, M.G. and Minetti, C. and Striano, P. and Pisciotta, L. and De Grandis, E. and Altmüller, J. and Weixler, L. and Nürnberg, P. and Thiele, H. and Yis, U. and Okur, T.D. and Polat, A.I. and Amiri, N. and Doosti, M. and Karimani, E.G. and Toosi, M.B. and Haddad, G. and Karakaya, M. and Wirth, B. and van Hagen, J.M. and Wolf, N.I. and Maroofian, R. and Houlden, H. and Cirak, S. and Gleeson, J.G.
Abstract:	ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation. Pharmacological inhibition of PARP also rescued the phenotype, suggesting the possibility of postnatal treatment for this genetic condition.
Keywords:	ADPRHL2, ARH3, ADP-Ribosylation, Poly-Adp Ribose, Oxidative Stress, Neurodegeneration, Epilepsy, Ataxia, Neuropathy, SUDEP
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Cell Press
Volume:	103
Number:	3
Page Range:	431-439
Date:	6 September 2018
Additional Information:	Erratum in: Am J Hum Genet 108(12):2385.
Official Publication:	https://doi.org/10.1016/j.ajhg.2018.07.010
PubMed:	View item in PubMed

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