Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome.

TitleBiallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome.
Publication TypeJournal Article
Year of Publication2018
AuthorsGhosh, SG, Becker, K, Huang, H, Dixon-Salazar, T, Chai, G, Salpietro, V, Al-Gazali, L, Waisfisz, Q, Wang, H, Vaux, KK, Stanley, V, Manole, A, Akpulat, U, Weiss, MM, Efthymiou, S, Hanna, MG, Minetti, C, Striano, P, Pisciotta, L, De Grandis, E, Altmüller, J, Nürnberg, P, Thiele, H, Yis, U, Okur, TDerya, Polat, AIpek, Amiri, N, Doosti, M, Karimani, EGhayoor, Toosi, MB, Haddad, G, Karakaya, M, Wirth, B, van Hagen, JM, Wolf, NI, Maroofian, R, Houlden, H, Cirak, S, Gleeson, JG
JournalAm J Hum Genet
Volume103
Issue3
Pagination431-439
Date Published2018 Sep 06
ISSN1537-6605
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.

DOI10.1016/j.ajhg.2018.07.010
Alternate JournalAm. J. Hum. Genet.
PubMed ID30100084
PubMed Central IDPMC6128219
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
MR/K000608/1 / / Medical Research Council / United Kingdom
R01 NS048453 / NS / NINDS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
R01 NS052455 / NS / NINDS NIH HHS / United States
T32 GM008666 / GM / NIGMS NIH HHS / United States
/ / Wellcome Trust / United Kingdom
F31 HD095602 / HD / NICHD NIH HHS / United States
G0601943 / / Medical Research Council / United Kingdom