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

Autor: Lara Paracchini, Luca Beltrame, Lucia Boeri, Federica Fusco, Paolo Caffarra, Sergio Marchini, Diego Albani, Gianluigi Forloni
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Alzheimer’s Research & Therapy, Vol 10, Iss 1, Pp 1-20 (2018)
Druh dokumentu: article
ISSN: 1758-9193
DOI: 10.1186/s13195-018-0435-2
Popis: Abstract Background 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. Methods We 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. Results 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. Conclusions These results support a role of exome sequencing for disease-associated variant discovery and reinforce available data on SEZ6 in AD models.
Databáze: Directory of Open Access Journals
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