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

Lara Paracchini, Luca Beltrame, Lucia Boeri, Federica Fusco, Paolo Caffarra, Sergio Marchini, Diego Albani, Gianluigi Forloni
2018
The 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. We describe a targeted exome
more » ... equencing 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. We 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. These results support a role of exome sequencing for disease-associated variant discovery and reinforce available data on SEZ6 in AD models.
doi:10.1186/s13195-018-0435-2 pmid:30309378 pmcid:PMC6182820 fatcat:xewpynxr4jcynmq4giyuxa3vt4