Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum.
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.
Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel. basel@post.tau.ac.il
Lina
L
Basel-Vanagaite
Tova
T
Hershkovitz
Eli
E
Heyman
Miquel
M
Raspall-Chaure
Naseebullah
N
Kakar
Pola
P
Smirin-Yosef
Marta
M
Vila-Pueyo
Liora
L
Kornreich
Holger
H
Thiele
Harald
H
Bode
Irina
I
Lagovsky
Dvir
D
Dahary
Ami
A
Haviv
Monika Weisz
MW
Hubshman
Metsada
M
Pasmanik-Chor
Peter
P
Nürnberg
Doron
D
Gothelf
Christian
C
Kubisch
Mordechai
M
Shohat
Alfons
A
Macaya
Guntram
G
Borck
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003337:Corpus Callosum / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D013036:Spasms, Infantile / Q000235:genetics*
D009419:Nerve Tissue Proteins; C584145:SZT2 protein, human