Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Basel-Vanagaite, Lina UNSPECIFIED UNSPECIFIED UNSPECIFIED Hershkovitz, Tova UNSPECIFIED UNSPECIFIED UNSPECIFIED Heyman, Eli UNSPECIFIED UNSPECIFIED UNSPECIFIED Raspall-Chaure, Miguel UNSPECIFIED UNSPECIFIED UNSPECIFIED Kakar, Naseebullah UNSPECIFIED UNSPECIFIED UNSPECIFIED Smirin-Yosef, Pola UNSPECIFIED UNSPECIFIED UNSPECIFIED Vila-Pueyo, Marta UNSPECIFIED orcid.org/0000-0003-0652-2988 UNSPECIFIED Kornreich, Liora UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Bode, Harald UNSPECIFIED UNSPECIFIED UNSPECIFIED Lagovsky, Irina UNSPECIFIED UNSPECIFIED UNSPECIFIED Dahary, Dvir UNSPECIFIED UNSPECIFIED UNSPECIFIED Haviv, Ami UNSPECIFIED UNSPECIFIED UNSPECIFIED Hubshman, Monika Weisz UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasmanik-Chor, Metsada UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Gothelf, Doron UNSPECIFIED UNSPECIFIED UNSPECIFIED Kubisch, Christian UNSPECIFIED orcid.org/0000-0003-4220-0978 UNSPECIFIED Shohat, Mordechai UNSPECIFIED UNSPECIFIED UNSPECIFIED Macaya, Alfons UNSPECIFIED UNSPECIFIED UNSPECIFIED Borck, Guntram UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language GENE Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47609