TY - JOUR
T1 - Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum
AU - Basel-Vanagaite, Lina
AU - Hershkovitz, Tova
AU - Heyman, Eli
AU - Raspall-Chaure, Miquel
AU - Kakar, Naseebullah
AU - Smirin-Yosef, Pola
AU - Vila-Pueyo, Marta
AU - Kornreich, Liora
AU - Thiele, Holger
AU - Bode, Harald
AU - Lagovsky, Irina
AU - Dahary, Dvir
AU - Haviv, Ami
AU - Hubshman, Monika Weisz
AU - Pasmanik-Chor, Metsada
AU - Nürnberg, Peter
AU - Gothelf, Doron
AU - Kubisch, Christian
AU - Shohat, Mordechai
AU - Macaya, Alfons
AU - Borck, Guntram
N1 - Funding Information:
We thank the families for participating in this study and M. van der Knaap for reviewing MRI images. We thank G.J. Halpern for her help with editing the manuscript. The study was supported by the Adler Chair in Pediatric Cardiology at Tel Aviv University, the Israeli Ministry of Health Chief Scientist Foundation (grant 3-4963 to L.B.-V.), the Israeli Science Foundation (grant 558/09 to L.B.-V.), the German Federal Ministry of Education and Research (NGFNplus-EMINet to P.N. and C.K.), the EuroEPINOMICS program (Deutsche Forschungsgemeinschaft [DFG] grant NU50/8-1 to P.N.), the Ministerio de Ciencia y Competitividad at Instituto de Salud Carlos III (grant PI12/01005 to A.M.), the Agència de Gestió d’Ajuts Universitaris i de Recerca (grant SGR 2009/0078 to A.M.), and the DFG (to G.B.). D.D. and A.H. are the owners of Toldot Genetics Ltd.
PY - 2013/9/5
Y1 - 2013/9/5
N2 - Epileptic encephalopathies are genetically heterogeneous severe disorders in which epileptic activity contributes to neurological deterioration. We studied two unrelated children presenting with a distinctive early-onset epileptic encephalopathy characterized by refractory epilepsy and absent developmental milestones, as well as thick and short corpus callosum and persistent cavum septum pellucidum on brain MRI. Using whole-exome sequencing, we identified biallelic mutations in seizure threshold 2 (SZT2) in both affected children. The causative mutations include a homozygous nonsense mutation and a nonsense mutation together with an exonic splice-site mutation in a compound-heterozygous state. The latter mutation leads to exon skipping and premature termination of translation, as shown by RT-PCR in blood RNA of the affected boy. Thus, all three mutations are predicted to result in nonsense-mediated mRNA decay and/or premature protein truncation and thereby loss of SZT2 function. Although the molecular role of the peroxisomal protein SZT2 in neuronal excitability and brain development remains to be defined, Szt2 has been shown to influence seizure threshold and epileptogenesis in mice, consistent with our findings in humans. We conclude that mutations in SZT2 cause a severe type of autosomal-recessive infantile encephalopathy with intractable seizures and distinct neuroradiological anomalies.
AB - Epileptic encephalopathies are genetically heterogeneous severe disorders in which epileptic activity contributes to neurological deterioration. We studied two unrelated children presenting with a distinctive early-onset epileptic encephalopathy characterized by refractory epilepsy and absent developmental milestones, as well as thick and short corpus callosum and persistent cavum septum pellucidum on brain MRI. Using whole-exome sequencing, we identified biallelic mutations in seizure threshold 2 (SZT2) in both affected children. The causative mutations include a homozygous nonsense mutation and a nonsense mutation together with an exonic splice-site mutation in a compound-heterozygous state. The latter mutation leads to exon skipping and premature termination of translation, as shown by RT-PCR in blood RNA of the affected boy. Thus, all three mutations are predicted to result in nonsense-mediated mRNA decay and/or premature protein truncation and thereby loss of SZT2 function. Although the molecular role of the peroxisomal protein SZT2 in neuronal excitability and brain development remains to be defined, Szt2 has been shown to influence seizure threshold and epileptogenesis in mice, consistent with our findings in humans. We conclude that mutations in SZT2 cause a severe type of autosomal-recessive infantile encephalopathy with intractable seizures and distinct neuroradiological anomalies.
UR - http://www.scopus.com/inward/record.url?scp=84883823388&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2013.07.005
DO - 10.1016/j.ajhg.2013.07.005
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AN - SCOPUS:84883823388
SN - 0002-9297
VL - 93
SP - 524
EP - 529
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -