Basel-Vanagaite, Lina, Hershkovitz, Tova, Heyman, Eli, Raspall-Chaure, Miguel, Kakar, Naseebullah, Smirin-Yosef, Pola, Vila-Pueyo, Marta ORCID: 0000-0003-0652-2988, Kornreich, Liora, Thiele, Holger, Bode, Harald, Lagovsky, Irina, Dahary, Dvir, Haviv, Ami, Hubshman, Monika Weisz, Pasmanik-Chor, Metsada, Nuernberg, Peter, Gothelf, Doron, Kubisch, Christian ORCID: 0000-0003-4220-0978, Shohat, Mordechai, Macaya, Alfons and Borck, Guntram (2013). Biallelic SZT2 Mutations Cause Infantile Encephalopathy with Epilepsy and Dysmorphic Corpus Callosum. Am. J. Hum. Genet., 93 (3). S. 524 - 530. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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Abstract

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 MET. 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Basel-Vanagaite, LinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hershkovitz, TovaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heyman, EliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raspall-Chaure, MiguelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kakar, NaseebullahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smirin-Yosef, PolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vila-Pueyo, MartaUNSPECIFIEDorcid.org/0000-0003-0652-2988UNSPECIFIED
Kornreich, LioraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bode, HaraldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lagovsky, IrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dahary, DvirUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haviv, AmiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hubshman, Monika WeiszUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasmanik-Chor, MetsadaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gothelf, DoronUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kubisch, ChristianUNSPECIFIEDorcid.org/0000-0003-4220-0978UNSPECIFIED
Shohat, MordechaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Macaya, AlfonsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borck, GuntramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-476095
DOI: 10.1016/j.ajhg.2013.07.005
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 93
Number: 3
Page Range: S. 524 - 530
Date: 2013
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENEMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/47609

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