Exome sequencing in an Italian family with Alzheimer’s disease points to a role for seizure-related gene 6 (SEZ6) rare variant R615H

Abstract

BackgroundThe typical familial form of Alzheimer’s disease (FAD) accounts for about 5% of total Alzheimer’s disease (AD) cases. Presenilins (PSEN1 and PSEN2) and amyloid-β (A4) precursor protein (APP) genes carry all reported FAD-linked mutations. However, other genetic loci may be involved in AD. For instance, seizure-related gene 6 (SEZ6) has been reported in brain development and psychiatric disorders and is differentially expressed in the cerebrospinal fluid of AD cases.MethodsWe describe a targeted exome sequencing analysis of a large Italian kindred with AD, negative for PSEN and APP variants, that indicated the SEZ6 heterozygous mutation R615H is associated with the pathology.ResultsWe overexpressed R615H mutation in H4-SW cells, finding a reduction of amyloid peptide Aβ(1–42). Sez6 expression decreased with age in a mouse model of AD (3xTG-AD), but independently from transgene expression.ConclusionsThese results support a role of exome sequencing for disease-associated variant discovery and reinforce available data on SEZ6 in AD models.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0435-2) contains supplementary material, which is available to authorized users.

The emerging role of kainate receptor functional dysregulation in pain

“…Notably, SEZ6 proteins are widely expressed throughout the brain, and have been implicated in neurodevelopmental and psychiatric disorders. 111 It was shown that a lack of SEZ6 family proteins also impaired motor functions, short-term memory, and cognitive flexibility. 112 Most importantly, recent evidence suggested that SEZ6 is a driver of the onset of inflammatory hyperalgesia.…”

Childhood-Onset Schizophrenia: A Systematic Overview of Its Genetic Heterogeneity From Classical Studies to the Genomic Era

“…SEZ6 was predicted to be involved in neuronal maturation and plasticity (Miyazaki et al, 2006). Recently mutations and altered expression of this gene have been associated with Alzheimer's and Niemann-Pick disease (Causevic et al, 2018;Paracchini et al, 2018).…”

Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3

“…SEZ6 is linked to neurological and psychiatric diseases, but the underlying molecular mechanisms are little understood. Genetic variants of SEZ6 are linked to childhood‐onset schizophrenia (Thr229‐Thr231del) (Ambalavanan et al , ), intellectual disability (Arg657Gln) (Gilissen et al , ), and AD (Arg615His) (Paracchini et al , ). These mutations are localized within the SEZ6 ectodomain that interacts with GluK2 and/or GluK3.…”

“…For example, deletions in the SEZ6 ectodomain are found in childhood‐onset schizophrenia (Ambalavanan et al , ). Other genetic variants have been reported in intellectual disability (Gilissen et al , ), while the rare SEZ6 mutation R615H has been suggested to cause a familial form of AD (Paracchini et al , ). Consistent with the disease link, SEZ6‐deficient mice, which are viable and fertile, display an anxiety‐ and depression‐related behavior (Gunnersen et al , ).…”