Febrile seizures are associated with mutation of seizure‐related (SEZ) 6, a brain‐specific gene

Abstract

Genetic factors contribute significantly to the etiology of febrile seizures (FS), the most common type of seizures in childhood. However, in most patients with FS, the causative gene is unknown. The purpose of this study was to explore the relationship between human brain-specific gene SEZ-6 and FS. Through amplification of genomic DNA by PCR and sequencing of the resulting products, we screened 75 subjects for mutations in the coding region (17 exons) of the SEZ-6 gene. Fifteen subjects were healthy individuals and 60 subjects had FS. Patients with FS could be divided into sub-groups based on seizure type (42 simple and 18 complex) and family history (41 had a positive family history). All patients have been followed to date to evaluate seizure recurrence and the development of epilepsy. No mutations were found in healthy controls, but 21 of the patients with FS had mutations in SEZ-6, and the most common type of mutation was a heterozygous, cytosine insertion (frame shift mutation) at position 1435 of the cDNA. The mutation incidence was significantly higher in patients with complex FS (vs. simple FS) and in patients with a positive family history. Sixteen of 42 patients with simple FS experienced seizure recurrence during the 1-5-year follow-up period. Fifteen of 18 patients with complex FS also experienced a recurrence during this period. Among these patients with recurrences, five patients with simple FS and six patients with complex FS have developed epilepsy. The mutation incidence among these epileptic patients is 72.7%. The human SEZ-6 gene is related to the occurrence and development of FS and may be a novel candidate gene for epilepsy. Screening for mutations in SEZ-6 may be valuable in predicting FS recurrence or the development of epilepsy.

Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders

“…RODG1 mutations result in Kohlschütter-Tönz syndrome, a disorder that presents with epilepsy and developmental delay, both features found in children with autism [70]. Lastly, SEZ6 acts in dendritic arborization and has been associated with seizures in a Chinese cohort [71,72]. This category of genes, along with genes identified to carry alterations in more than one family, may be the most fruitful groups of novel ASD candidates for future investigations.…”

Cathepsin D and its newly identified transport receptor SEZ6L2 can modulate neurite outgrowth

“…Genetic variations in SEZ6, SEZ6L and SEZ6L2 (the seizure-related gene 6 family) have been associated with febrile seizures, bipolar disorder I and autism (albeit the latter has not been confirmed in a subsequent study), respectively (Yu et al, 2007;Kumar et al, 2009;Mulley et al, 2011;Konyukh et al, 2011;Xu et al, 2013). Anti-SEZ6L2 antibodies have also been detected in a patient suffering from cerebellar ataxia and retinopathy (Yaguchi et al, 2014).…”

The relevance of individual genetic background and its role in animal models of epilepsy

“…The vast majority of mouse models in use to study genetic influences on seizures and seizure-induced cell death are reverse genetic models in which a single gene is identified for study based on its known function or known involvement in human epilepsy and then it is manipulated in a mouse. Results from a number of studies (Ferraro et al, 2010; Mohajeri et al, 2004; Schauwecker, 2000; Yagi et al, 2009; Yu et al, 2007) clearly demonstrate that the genetic backgrounds of targeted mutants used in epilepsy research can affect susceptibility to seizures (Table 1) and its neuropathological consequences (Table 2) and must be carefully controlled.…”