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Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum

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Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum. / Basel-Vanagaite, Lina; Hershkovitz, Tova; Heyman, Eli; Raspall-Chaure, Miquel; Kakar, Naseebullah; Smirin-Yosef, Pola; Vila-Pueyo, Marta; Kornreich, Liora; Thiele, Holger; Bode, Harald; Lagovsky, Irina; Dahary, Dvir; Haviv, Ami; Hubshman, Monika Weisz; Pasmanik-Chor, Metsada; Nürnberg, Peter; Gothelf, Doron; Kubisch, Christian; Shohat, Mordechai; Macaya, Alfons; Borck, Guntram.

In: AM J HUM GENET, Vol. 93, No. 3, 05.09.2013, p. 524-9.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Basel-Vanagaite, L, Hershkovitz, T, Heyman, E, Raspall-Chaure, M, Kakar, N, Smirin-Yosef, P, Vila-Pueyo, M, Kornreich, L, Thiele, H, Bode, H, Lagovsky, I, Dahary, D, Haviv, A, Hubshman, MW, Pasmanik-Chor, M, Nürnberg, P, Gothelf, D, Kubisch, C, Shohat, M, Macaya, A & Borck, G 2013, 'Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum', AM J HUM GENET, vol. 93, no. 3, pp. 524-9. https://doi.org/10.1016/j.ajhg.2013.07.005

APA

Basel-Vanagaite, L., Hershkovitz, T., Heyman, E., Raspall-Chaure, M., Kakar, N., Smirin-Yosef, P., Vila-Pueyo, M., Kornreich, L., Thiele, H., Bode, H., Lagovsky, I., Dahary, D., Haviv, A., Hubshman, M. W., Pasmanik-Chor, M., Nürnberg, P., Gothelf, D., Kubisch, C., Shohat, M., ... Borck, G. (2013). Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum. AM J HUM GENET, 93(3), 524-9. https://doi.org/10.1016/j.ajhg.2013.07.005

Vancouver

Basel-Vanagaite L, Hershkovitz T, Heyman E, Raspall-Chaure M, Kakar N, Smirin-Yosef P et al. Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum. AM J HUM GENET. 2013 Sep 5;93(3):524-9. https://doi.org/10.1016/j.ajhg.2013.07.005

Bibtex

@article{51fb8c463a2a492f9f55a283f546df90,
title = "Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum",
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 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.",
keywords = "Alleles, Amino Acid Sequence, Animals, Base Sequence, Child, Child, Preschool, Corpus Callosum, Female, Genetic Predisposition to Disease, Heterozygote, Homozygote, Humans, Infant, Magnetic Resonance Imaging, Male, Mice, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Pedigree, Spasms, Infantile",
author = "Lina Basel-Vanagaite and Tova Hershkovitz and Eli Heyman and Miquel Raspall-Chaure and Naseebullah Kakar and Pola Smirin-Yosef and Marta Vila-Pueyo and Liora Kornreich and Holger Thiele and Harald Bode and Irina Lagovsky and Dvir Dahary and Ami Haviv and Hubshman, {Monika Weisz} and Metsada Pasmanik-Chor and Peter N{\"u}rnberg and Doron Gothelf and Christian Kubisch and Mordechai Shohat and Alfons Macaya and Guntram Borck",
note = "Copyright {\textcopyright} 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
year = "2013",
month = sep,
day = "5",
doi = "10.1016/j.ajhg.2013.07.005",
language = "English",
volume = "93",
pages = "524--9",
journal = "AM J HUM GENET",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",

}

RIS

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 - Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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.

KW - Alleles

KW - Amino Acid Sequence

KW - Animals

KW - Base Sequence

KW - Child

KW - Child, Preschool

KW - Corpus Callosum

KW - Female

KW - Genetic Predisposition to Disease

KW - Heterozygote

KW - Homozygote

KW - Humans

KW - Infant

KW - Magnetic Resonance Imaging

KW - Male

KW - Mice

KW - Molecular Sequence Data

KW - Mutation

KW - Nerve Tissue Proteins

KW - Pedigree

KW - Spasms, Infantile

U2 - 10.1016/j.ajhg.2013.07.005

DO - 10.1016/j.ajhg.2013.07.005

M3 - SCORING: Journal article

C2 - 23932106

VL - 93

SP - 524

EP - 529

JO - AM J HUM GENET

JF - AM J HUM GENET

SN - 0002-9297

IS - 3

ER -