TY - JOUR
T1 - Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome
AU - Ghosh, Shereen G.
AU - Becker, Kerstin
AU - Huang, He
AU - Dixon-Salazar, Tracy
AU - Chai, Guoliang
AU - Salpietro, Vincenzo
AU - Al-Gazali, Lihadh
AU - Waisfisz, Quinten
AU - Wang, Haicui
AU - Vaux, Keith K.
AU - Stanley, Valentina
AU - Manole, Andreea
AU - Akpulat, Ugur
AU - Weiss, Marjan M.
AU - Efthymiou, Stephanie
AU - Hanna, Michael G.
AU - Minetti, Carlo
AU - Striano, Pasquale
AU - Pisciotta, Livia
AU - de Grandis, Elisa
AU - Altmüller, Janine
AU - Nürnberg, Peter
AU - Thiele, Holger
AU - Yis, Uluc
AU - Okur, Tuncay Derya
AU - Polat, Ayse Ipek
AU - Amiri, Nafise
AU - Doosti, Mohammad
AU - Karimani, Ehsan Ghayoor
AU - Toosi, Mehran B.
AU - Haddad, Gabriel
AU - Karakaya, Mert
AU - Wirth, Brunhilde
AU - van Hagen, Johanna M.
AU - Wolf, Nicole I.
AU - Maroofian, Reza
AU - Houlden, Henry
AU - Cirak, Sebahattin
AU - Gleeson, Joseph G.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85054734998&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30100084
U2 - https://doi.org/10.1016/j.ajhg.2018.07.010
DO - https://doi.org/10.1016/j.ajhg.2018.07.010
M3 - Article
C2 - 30100084
VL - 103
SP - 431
EP - 439
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 3
ER -