Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment.
Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes are associated with early-onset familial Alzheimer's disease (EOAD). There are several reports describing mutations in PSEN1 in cases with frontotemporal dementia (FTD). We identified two novel mutations in the PSEN1 gene: L226F and L424H. The first mutation was detected in a patient with a clinical diagnosis of FTD and a post-mortem diagnosis of AD. The second mutation is connected with a clinical phenotype of variant AD with strong FTD signs. In silico modeling revealed that the mutations, as well as mutations used for comparison (F177L and L424R), change the local structure, stability and/or properties of the transmembrane regions of the presenilin 1 protein (PS1). In contrast, a silent non-synonymous substitution F175S is eclipsed by external residues and has no influence on PS1 interfacial surface. We suggest that in silico analysis of PS1 substitutions can be used to characterize novel PSEN1 mutations, to discriminate between silent polymorphisms and a potential disease-causing mutation. We also propose that PSEN1 mutations should be considered in FTD patients with no MAPT mutations.
Department of Neurodegenerative Disorders, Medical Research Center, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warszawa, Poland. czarekz@cmdik.pan.pl
Cezary
C
Zekanowski
Maciej P
MP
Golan
Krystiana A
KA
Krzyśko
Wanda
W
Lipczyńska-Łojkowska
Sławomir
S
Filipek
Anna
A
Kowalska
Grzegorz
G
Rossa
Beata
B
Pepłońska
Maria
M
Styczyńska
Aleksandra
A
Maruszak
Dorota
D
Religa
Mieczysław
M
Wender
Jerzy
J
Kulczycki
Maria
M
Barcikowska
Jacek
J
Kuźnicki
D000328:Adult; D019295:Computational Biology / Q000379:methods; D003704:Dementia / Q000175:diagnosis / Q000235:genetics*; D003937:Diagnosis, Differential; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D053764:Presenilin-1
D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1