A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimerʼs disease and leads to death as early as the age of 28 years

Abstract

The majority of early-onset familial Alzheimer's disease (FAD) is associated with mutations in the presenilin-1 (PS1) gene. We describe a novel Polish PS1 mutation of Pro117Leu, associated with the earliest average age of onset and death so far reported in a PS-linked, FAD kindred. Human kidney 293 and mouse neuroblastoma N2a cells were stably transfected with wild-type and PS1 P117L. There was a significant increase in the amyloid beta42/40 ratio in the N2a P117L PS1 transfected cells compared with N2a transfected with wild-type PS1. What role PS has in the pathogenesis of AD remains to be determined, however, the severity of the clinical picture associated with this PS1 mutation stresses the importance of presenilin.

Novel presenilin 1 variant (P117A) causing Alzheimer's disease in the fourth decade of life

“…This finding is clearly consistent with the observation of increased Aβ42/total Aβ ratio in several other known PSEN1 AD mutations, including P117L [8] and P177S [2] and suggests that this mutation causes AD via a similar mechanism. These findings reiterate the central role of PSEN1 in AD and add to the list of known disease causing variants in PSEN1.…”

“…Codon 117 is located in the first hydrophilic loop of the PSEN1 protein [6] and is the site of three other disease-causing variants [8,11]. No variants that segregate with disease were found elsewhere in the PSEN1 gene in members of this family.…”

“…Three disease-causing variants at codon 117 of PSEN1 have been described previously. The P117L mutation was described in a single family with onset between 24 and 34 years [8]. The P117R variant was identified in a female patient, who has had complaints of memory loss beginning at 36 years of age [11].…”

“…Most of these variants occur in transmembrane regions of PSEN1 and appear to alter the production and deposition of 42 amino acid Aβ fragments (Aβ42) [10]. Thirteen variants, including P117L, P117R and P117S occur in the first hydrophilic loop of PSEN1 [2,6,8,11 ]. In this study we sequenced PSEN1 in a family with EOAD and identified a novel variant which segregates with AD.…”

The Correlation between Genotype and Phenotype of Alzheimer's Disease

“…The earliest reported AAO was 20 years in a family with p.P436Q mutation [6]. There are also some family members with the mutation p.P117A [74,75], p.P117L [76][77][78] and p.L173W [79] have recently been recorded with onset at 24 years. Very early onset of cognitive decline, before age 30 years, has been noted with the following PSEN-1 mutations: p.L85P [80], p.T116N [81][82][83][84], p.P117S [77], p.I143T [82,83,[85][86][87], InsFI [82,88], p.L166H [89], p.S169L [90,91], p.S170F [92][93][94], p.G209V [95], p.M233V [96], p.M233I [97], p.L235Pr [98], p.Y256S [99], p.A260V [39,100], p.V272A [84,101], p.L381V [102], p.G384A [85], p.L424R [103], and p.A434C [82].…”